ALBERT

Description:    The sublimation of glycyl-L-α-alanine (Gly-Ala), L-α-alanyl-L-α-alanine (Ala-Ala), and DL-α-alanyl-DL-α-valine (Ala-Val) aliphatic dipeptides is studied by electron ionization mass spectrometry in combination with Knudsen effusion. The temperature range in which substances sublime as monomer molecular forms is determined. Enthalpies of sublimation Δ s H °( T ) are determined for Gly-Ala, Ala-Ala, and Ala-Val. It is shown that the enthalpy of sublimation of dipeptides increases with an increase in the side hydrocarbon radical. The unknown Δ s H °(298) values for 17 amino acids and nine dipeptides are estimated using the proposed “structure-property” correlation model, in which the geometry and electron characteristics of molecules are used as structural descriptors. Content Type Journal Article Category Physical Chemistry of Surface Phenomena Pages 457-462 DOI 10.1134/S0036024412030065 Authors V. G. Badelin, Institute of Chemistry of Solutions, Russian Academy of Sciences, Ivanovo, 153045 Russia E. Yu. Tyunina, Ivanovo State University of Chemical Technology, Ivanovo, 153000 Russia A. V. Krasnov, Ivanovo State University of Chemical Technology, Ivanovo, 153000 Russia V. V. Tyunina, Ivanovo State University of Chemical Technology, Ivanovo, 153000 Russia N. I. Giricheva, Ivanovo State University, Ivanovo, 153025 Russia A. V. Girichev, Ivanovo State University of Chemical Technology, Ivanovo, 153000 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 3

Description:    The acid-base properties of metal acetylacetonates and chromatographic sorbents on the basis of Chromaton N with deposited combined stationary phases from polyethylene glycol (PEG 20M) and nickel(II) and iron(III) acetylacetonates have been investigated by means of pH measurement and Hammett indicator adsorption. The change of the acid-base state of the surface of Chromaton N depending on the nature of a metal of the modifying additive, the complex structure, and the deposition method has been demonstrated. Content Type Journal Article Category Physical Chemistry of Surface Phenomena Pages 463-467 DOI 10.1134/S0036024412030272 Authors Yu. G. Slizhov, Tomsk State University, Tomsk, 634050 Russia T. N. Matveev, Tomsk State University, Tomsk, 634050 Russia T. S. Minakova, Tomsk State University, Tomsk, 634050 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 3

Description:    The properties of the porous polymer Dowex L-285, modified by 5-hydroxy-6-methyluracil, are investigated by means of gas chromatography. It is found that the modification leads to a considerable increase in the sorption activity of the porous polymer with respect to both polar and nonpolar molecules. It is shown that each type of cavities in the supramolecular structure of 5-hydroxy-6-methyluracil contributes to the adsorption and thermodynamic properties of the modified adsorbent. Content Type Journal Article Category Physical Chemistry of Separation Processes: Chromatography Pages 475-478 DOI 10.1134/S0036024412030132 Authors V. Yu. Gus’kov, Bashkir State University, Ufa, 450074 Russia S. P. Ivanov, Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, Ufa, 450054 Russia R. A. Khabibullina, Bashkir State University, Ufa, 450074 Russia R. R. Garafutdinov, Institute of Biochemistry and Genetics, Ufa Scientific Center, Russian Academy of Sciences, Ufa, 450054 Russia F. Kh. Kudasheva, Bashkir State University, Ufa, 450074 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 3

Description:    Extranodal natural killer/T-cell lymphoma (ENKL) has a dismal prognosis. Although L-asparaginase has shown promising efficacy as a frontline therapy, currently there are no treatment options after progression to an L-asparaginase-containing regimen. We report the results of gemcitabine-containing therapy in patients with relapsed or refractory ENKL. We retrospectively reviewed 20 patients with refractory or relapsed ENKL who received a gemcitabine-containing regimen between 2005 and 2011. The overall response rate was 40 % (8 of 20 patients) with a complete response (CR) rate of 20 % ( n  = 4) and a partial response (PR) rate of 20 % ( n  = 4). Four complete responders had a disease-free status for more than 7 months including two patients received autologous stem cell transplantation consolidation and L-aspraginase maintenance, respectively. The median progression-free survival of the 20 patients was 2.3 months; however, it was 7.3 months for eight responders (CR and PR). The median overall survival of the eight responders had not been reached at the time of analysis. Gemcitabine was effective in a subset of pretreated ENKL patients and can be considered as a salvage option. Content Type Journal Article Category SHORT REPORT Pages 1-4 DOI 10.1007/s10637-012-9889-4 Authors Hee Kyung Ahn, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea Seok Jin Kim, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710 Republic of Korea Deok Won Hwang, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710 Republic of Korea Young Hyeh Ko, Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Tiffany Tang, Department of Medical Oncology, National Cancer Center, Singapore, Singapore Soon Thye Lim, Department of Medical Oncology, National Cancer Center, Singapore, Singapore Won Seog Kim, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710 Republic of Korea Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description: Erratum to: Silymarin attenuated mast cell recruitment thereby decreased the expressions of matrix metalloproteinases-2 and 9 in rat liver carcinogenesis Content Type Journal Article Category Erratum Pages 1-2 DOI 10.1007/s10637-012-9892-9 Authors Gopalakrishnan Ramakrishnan, Department of Biochemisty, University of Madras, Guindy Campus, Chennai, 600025 Tamilnadu, India Sundaram Jagan, Department of Biochemisty, University of Madras, Guindy Campus, Chennai, 600025 Tamilnadu, India Sattu Kamaraj, Department of Biochemisty, University of Madras, Guindy Campus, Chennai, 600025 Tamilnadu, India Pandi Anandakumar, Department of Biochemisty, University of Madras, Guindy Campus, Chennai, 600025 Tamilnadu, India Thiruvengadam Devaki, Department of Biochemisty, University of Madras, Guindy Campus, Chennai, 600025 Tamilnadu, India Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    In this research a new idea for prediction of ultimate sizes of bimetallic nanocomposites synthesized in water-in-oil microemulsion system is proposed. In this method, by modifying Tabor Winterton approximation equation, an effective Hamaker constant was introduced. This effective Hamaker constant was applied in the van der Waals attractive interaction energy. The obtained effective van der Waals interaction energy was used as attractive contribution in the total interaction energy. The modified interaction energy was applied successfully to predict some bimetallic nanoparticles, at different mass fraction, synthesized in microemulsion system of dioctyl sodium sulfosuccinate (AOT)/isooctane. Content Type Journal Article Category Physical Chemistry of Nanoclusters and Nanomaterials Pages 2014-2017 DOI 10.1134/S003602441213002X Authors Alireza Salabat, Department of Chemistry, Faculty of Science, Arak University, P. O. Box 38156-8-8349, Arak, Iran Hassan Saydi, Department of Chemistry, Faculty of Science, Arak University, P. O. Box 38156-8-8349, Arak, Iran Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 13

Description:    Densities, viscosities, refractive indices and ultrasonic velocities of the binary mixtures of acetophenone with ethyl acetate were measured over the entire mole fractions at 303.15, 313.15, and 323.15 K. From the experimental results, excess molar volumes V E , viscosity deviation Δ η , refractive index deviation Δ n D , deviations in isentropic compressibility Δκ s and excess intermolecular free length Δ L f are calculated. The viscosity values were fitted to the models of Krishnan-Laddha and McAllister. The thermophysical properties under study were fit to the Jouyban-Acree model. The excess values were correlated using Redlich-Kister polynomial equation to obtain their coefficients and standard deviations. The data obtained fitted with the values correlated by the corresponding models very well. The results are interpreted in terms of molecular interactions occurring in the solution. Content Type Journal Article Category Physical Chemistry of Solutions Pages 1947-1952 DOI 10.1134/S0036024412130195 Authors K. Saravanakumar, Department of Chemical Engineering, Sathyabama University, Chennai, 600119 India R. Baskaran, Department of Chemical Engineering, St. Joseph’s College of Engineering, Chennai-119, India T. R. Kubendran, Department of Chemical Engineering, A.C. College of Technology, Anna University, Chennai, 600025 India Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 13

Description:    The solubilities in the KCl-MgCl 2 -H 2 O system were determined at 50 and 75°C and the phase diagrams and the diagram of refractive index vs composition were plotted. Two invariant point, three univariant curves, and three crystallization zones, corresponding to potassium chloride, hexahydrate (MgCl 2 · 6H 2 O) and double salt (KCl · MgCl 2 · 6H 2 O) showed up in the phase diagrams of the ternary system, The mixing parameters θ K, Ca and Ψ K, Ca, Cl and equilibrium constant K sp were evaluated in KCl-MgCl 2 -H 2 O system by least-squares optimization procedure, in which the single-salt Pitzer parameters of KCl and MgCl 2 β (0) , β (1) , β (2) , and C ϕ were directly calculated from the literature. The results obtained were in good agreement with the experimental data. Content Type Journal Article Category Physical Chemistry of Solutions Pages 1930-1935 DOI 10.1134/S0036024412130146 Authors Ji-min Yang, School of Chemistry & Resources and Environment, Linyi University, Linyi, 276005 China Jing Peng, School of Chemistry & Resources and Environment, Linyi University, Linyi, 276005 China Yu-xia Duan, School of Chemistry & Resources and Environment, Linyi University, Linyi, 276005 China Chong Tian, School of Chemistry & Resources and Environment, Linyi University, Linyi, 276005 China Mei Ping, Experimental Centre, Linyi University, Linyi, 276005 China Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 13

Description:    The insertion reactions of the germylenoid H 2 GeClMgCl with RH (R = F, OH, NH 2 ) have been studied by using the DFT B3LYP and QCISD methods. The geometries of the stationary points on the potential energy surfaces of the reactions were optimized at the B3LYP/6-311+G( d , p ) level of theory. The calculated results indicate that all the mechanisms of the three insertion reactions are identical to each other. The QCISD/6-311++G( d , p )//B3LYP/6-311+G( d , p ) calculated potential energy barriers for the three insertion reactions of R = F, OH, and NH 2 are 164.62, 193.30, and 200.73 kJ mol −1 , and the reaction energies for the three reactions are −57.46, −35.65, and −22.22 kJ mol −1 , respectively. Under the same situation, the insertion reactions should occur easily in the following order H-F 〉 H-OH 〉 H-NH 2 . In THF solvent the insertion reactions get more difficult than in gas phase. Content Type Journal Article Category Structure of Matter and Quantum Chemistry Pages 1969-1973 DOI 10.1134/S0036024412130225 Authors Wen-Zuo Li, College of Chemistry and Chemical Engineering, Yantai University, Yantai, 264005 P. R. China Yu-Wei Pei, College of Chemistry and Chemical Engineering, Yantai University, Yantai, 264005 P. R. China Jian-Bo Cheng, College of Chemistry and Chemical Engineering, Yantai University, Yantai, 264005 P. R. China Qing-Zhong Li, College of Chemistry and Chemical Engineering, Yantai University, Yantai, 264005 P. R. China Bao-An Gong, College of Chemistry and Chemical Engineering, Yantai University, Yantai, 264005 P. R. China Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 13

Description:    The gas-phase reaction of palladium atom with acetone is investigated using density functional theory. Geometries and energies of the reactants, intermediates, and products involved are calculated. Both ground and excited state potential energy surfaces are investigated in detail. The present results show that the title reaction start with the formation of an η 2 -CH 3 COCH 3 -metal complex, followed by C-O, C-H, and C-C activation. These reactions can lead to four different products (PdO + C 3 H 6 , PdCH 2 COCH 3 + H, PdCH 2 + CH 3 CHO, and PdCOCH 2 + CH 4 ). The present results may be helpful in understanding the mechanism of the title reaction and further experimental investigation of the reaction. Content Type Journal Article Category Structure of Matter and Quantum Chemistry Pages 1982-1990 DOI 10.1134/S0036024412130092 Authors Guo-Liang Dai, School of Pharmaceutical and Chemical Engineering, Taizhou University, Linhai, 317000 China Chuan-Feng Wang, School of Pharmaceutical and Chemical Engineering, Taizhou University, Linhai, 317000 China Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 13

Description:    In this paper, biomimetic synthesis of calcium carbonate (CaCO 3 ) in the presence of biomolecules of two vegetables-tomato and capsicum is investigated. Scanning electron microscopy and X-ray powder diffractometry were used to characterize the CaCO 3 obtained. The biomolecules in the extracts of two vegetables are determined by UV-vis or FTIR. The results indicate that a mixture of calcite and vaterite spheres constructed from small particles is produced with the extract of tomato, while aragonite rods or ellipsoids are formed in the presence of extract of capsicum. The possible formation mechanism of the CaCO 3 crystals with tomato biomolecules can be interpreted by particle-aggregation based non-classical crystallization laws. The proteins and/or other biomolecules in tomato and capsicum may control the formation of vaterite and aragonite crystals by adsorbing onto facets of them. Content Type Journal Article Category Biophysical Chemistry Pages 2071-2075 DOI 10.1134/S003602441213016X Authors Long Chen, Department of Chemistry, Huangshan University, Huangshan, 245041 P. R. China Wang-Hua Xu, School of Chemistry and Chemical Engineering, Anqing Teachers College, Anqing, 246011 P. R. China Ying-Guo Zhao, School of Chemistry and Chemical Engineering, Anqing Teachers College, Anqing, 246011 P. R. China Yan Kang, Department of Chemistry, Huangshan University, Huangshan, 245041 P. R. China Shao-Hua Liu, Department of Chemistry, Huangshan University, Huangshan, 245041 P. R. China Zai-Yong Zhang, Department of Chemistry, Huangshan University, Huangshan, 245041 P. R. China Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 13

Description:    The Er 3+ :Y 3 Al 5 O 12 , an upconversion luminescence agent, which is able to transform the visible light to ultraviolet light, was synthesized by nitrate-citric acid method. And then, a novel photocatalyst, Er 3+ :Y 3 Al 5 O 12 /ZnO composites, was prepared by ultrasonic dispersing and liquid boil method. X-ray diffraction (XRD) and scanning electron microscopy (SEM) were used to characterize the structural morphology and surface properties of the Er 3+ :Y 3 Al 5 O 12 /ZnO. Azo Fuchsine dye was selected as target organic pollutant to inspect the photocatalytic activity of Er 3+ :Y 3 Al 5 O 12 /ZnO. The key parameters affecting the photocatalytic activity of Er 3+ :Y 3 Al 5 O 12 /ZnO, such as Er 3+ :Y 3 Al 5 O 12 content, heat-treatment temperature and heat-treatment time, were studied. In addition, the effects of dye initial concentration, Er 3+ :Y 3 Al 5 O 12 /ZnO amount and solar light irradiation time were also reviewed, as well as the photocatalytic activity in degradation of other organic dyes were compared. It was found that the photocatalytic activity of Er 3+ :Y 3 Al 5 O 12 /ZnO was much superior to pure ZnO under the same conditions. Thus, the Er 3+ :Y 3 Al 5 O 12 /ZnO is a useful photocatalyst for the wastewater treatment because it can efficiently utilize solar light by converting visible light into ultraviolet light. Content Type Journal Article Category Photochemistry and Magnetochemistry Pages 2049-2056 DOI 10.1134/S0036024412130262 Authors L. N. Yin, College of Chemistry, Liaoning University, Shenyang, 110036 P. R. China Y. Li, College of Chemistry, Liaoning University, Shenyang, 110036 P. R. China J. Wang, College of Chemistry, Liaoning University, Shenyang, 110036 P. R. China Y. M. Kong, College of Pharmacy, Liaoning University, Shenyang, 110036 P. R. China Y. Zhai, College of Chemistry, Liaoning University, Shenyang, 110036 P. R. China B. X. Wang, College of Chemistry, Liaoning University, Shenyang, 110036 P. R. China K. Li, College of Chemistry, Liaoning University, Shenyang, 110036 P. R. China X. D. Zhang, College of Chemistry, Liaoning University, Shenyang, 110036 P. R. China Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 13

Description:    In this work, we report the formation of leaf-like ZnO nanoflakes by anodization of zinc foil in a mixture of ammonium sulfate and sodium hydroxide electrolytes under various applied voltage and concentration of sodium hydroxide. The morphology and structure of ZnO nanoflakes were investigated by field emission scanning electron microscopy, energy-dispersive X-ray spectroscopy and X-ray diffraction analysis. In addition, the photocatalytic activity of the prepared nanoflakes zinc oxide was evaluated in the photodegradation of organic dye methylene blue (MB) solution under UV irradiation. It was found that zinc oxide prepared under high concentration of sodium hydroxide and high voltage showed better performance in the photodegradation of methylene blue. Content Type Journal Article Category Photochemistry and Magnetochemistry Pages 2041-2048 DOI 10.1134/S0036024412130171 Authors Muhammad Akhyar Farrukh, Department of Chemistry, GC University Lahore, Lahore, 54000 Pakistan Chin-Kiat Thong, School of Chemical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia Rohana Adnan, School of Chemical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia Mohd Amirrul Kamarulzaman, School of Chemical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 13

Description:    Objective Certain eligibility criteria for Phase 1 cancer clinical trials may impede successful patient enrollment onto a study. We evaluated patient-specific or study-specific reasons for screen failures on Phase 1 oncology clinical trials and discuss factors which may inhibit subject enrollment. Methods Thirty-eight Phase 1 clinical trials for solid tumors meeting eligibility criteria and opened for enrollment between February 2006 and February 2011 at one oncology Phase 1 program were examined. Categorical reasons for screen failures and patients’ demographics were examined and compared to characteristics of patients that successfully enrolled on a Phase 1 trial. Results There were a total of 583 successful Phase 1 enrollment and dose administration events out of 773 Phase 1 consent events (75.4 % dose success rate). The three most common reasons for screen failure were: out of protocol-specified range for chemistry, development of an interval medical issue that precluded proceeding with study participation, and subject declining participation after signing consent. Living further away from the Phase 1 program and receipt of fewer prior lines of systemic chemotherapy were significantly associated with increased screen failures. Conclusion Screen failures for Phase 1 studies are not uncommon (24.6 %). When a protocol required tumor or host analyte is not required, most screen failures are due to out of protocol-specified range for chemistry or the development of an interval medical issue. Screen failure rates were increased when patients had longer travel distances and fewer prior lines of systemic chemotherapy. Content Type Journal Article Category SHORT REPORT Pages 1-6 DOI 10.1007/s10637-012-9894-7 Authors Alexandra Mckane, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, 10510 N 92nd St. Ste 200, Scottsdale, AZ 85258, USA Chao Sima, The Translational Genomics Research Institute, Phoenix, AZ, USA Ramesh K. Ramanathan, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, 10510 N 92nd St. Ste 200, Scottsdale, AZ 85258, USA Gayle Jameson, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, 10510 N 92nd St. Ste 200, Scottsdale, AZ 85258, USA Cathy Mast, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, 10510 N 92nd St. Ste 200, Scottsdale, AZ 85258, USA Erica White, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, 10510 N 92nd St. Ste 200, Scottsdale, AZ 85258, USA Sharon Fleck, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, 10510 N 92nd St. Ste 200, Scottsdale, AZ 85258, USA Molly Downhour, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, 10510 N 92nd St. Ste 200, Scottsdale, AZ 85258, USA Daniel D. Von Hoff, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, 10510 N 92nd St. Ste 200, Scottsdale, AZ 85258, USA Glen J. Weiss, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, 10510 N 92nd St. Ste 200, Scottsdale, AZ 85258, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Withaferin A (WA), a steroidal lactone derived from the plant Vassobia breviflora , has been reported to have anti-proliferative, pro-apoptotic, and anti-angiogenic properties against cancer growth. In this study, we identified several key underlying mechanisms of anticancer action of WA in glioblastoma cells. WA was found to inhibit proliferation by inducing a dose-dependent G2/M cell cycle arrest and promoting cell death through both intrinsic and extrinsic apoptotic pathways. This was accompanied by an inhibitory shift in the Akt/mTOR signaling pathway which included diminished expression and/or phosphorylation of Akt, mTOR, p70 S6K, and p85 S6K with increased activation of AMPKα and the tumor suppressor tuberin/TSC2. Alterations in proteins of the MAPK pathway and cell surface receptors like EGFR, Her2/ErbB2, and c-Met were also observed. WA induced an N-acetyl-L-cysteine-repressible enhancement in cellular oxidative potential/stress with subsequent induction of a heat shock stress response primarily through HSP70, HSP32, and HSP27 upregulation and HSF1 downregulation. Taken together, we suggest that WA may represent a promising chemotherapeutic candidate in glioblastoma therapy warranting further translational evaluation. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-13 DOI 10.1007/s10637-012-9888-5 Authors Patrick T. Grogan, Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas, KS 66160, USA Kristina D. Sleder, Department of Surgery, University of Kansas Medical Center, Kansas, KS 66160, USA Abbas K. Samadi, Department of Surgery, University of Kansas Medical Center, Kansas, KS 66160, USA Huaping Zhang, Department of Medicinal Chemistry, University of Kansas School of Pharmacy, Lawrence, KS 66045, USA Barbara N. Timmermann, Department of Medicinal Chemistry, University of Kansas School of Pharmacy, Lawrence, KS 66045, USA Mark S. Cohen, Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas, KS 66160, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Introduction As angiogenic pathways have become important targets for inhibition of tumor growth, we examined the concept of dual pathway blockade by small-molecule tyrosine kinase inhibitors targeting vascular endothelial and epidermal growth factor receptors. Methods Escalating doses of pazopanib (400–800 mg once daily [QD]) plus erlotinib (100–150 mg QD) doses were evaluated in cohorts of 3–6 adults with advanced solid tumors. Twelve additional patients were enrolled in an expansion cohort to confirm the maximum tolerated dose (MTD). Results The MTD, defined during assessment of 20 patients, was pazopanib 600 mg plus erlotinib 150 mg. Two dose-limiting toxicities, rash and elevated liver enzymes, occurred at pazopanib 800 mg and erlotinib 150 mg. Overall, 30 % and 27 % of patients required dose interruption of pazopanib or erlotinib, respectively; 15 % of patients required a dose reduction of erlotinib to manage toxicities. The most common adverse events in patients treated with any dose regimen of pazopanib plus erlotinib ( N  = 33) were diarrhea, rash, nausea, and decreased appetite. The adverse-event profile of the combination did not appear to differ from that of each compound administered alone. Coadministration of pazopanib 600 mg QD and erlotinib 150 mg QD did not consistently affect the pharmacokinetics of either compound relative to that observed for either compound administered alone. Of 26 patients evaluated for efficacy, 3 (12 %; all non-small-cell lung cancer) had partial response and 10 (38 %) had stable disease. Conclusions Concomitant administration of pazopanib 600 mg and erlotinib 150 mg is feasible, with a manageable toxicity profile. These results support further clinical development of the pazopanib-erlotinib combination. Content Type Journal Article Category PHASE I STUDIES Pages 1-9 DOI 10.1007/s10637-012-9887-6 Authors Grace K. Dy, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA Jeffrey R. Infante, Sarah Cannon Research Institute, 250 25th Avenue North, Suite 200, Nashville, TN 37203, USA S. Gail Eckhardt, Division of Medical Oncology, University of Colorado School of Medicine, 13001 E 17th Place, Aurora, CO 80045, USA Silvia Novello, Department of Clinical & Biological Sciences, University of Turin, Auo San Luigi-Regione Gonzole 10, 10043 Orbassano, Torino, Italy Wen Wee Ma, Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA Suzanne F. Jones, Sarah Cannon Research Institute, 250 25th Avenue North, Suite 200, Nashville, TN 37203, USA Anne Huff, GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, Collegeville, PA 19426, USA Qiong Wang, GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, Collegeville, PA 19426, USA A. Benjamin Suttle, GlaxoSmithKline Pharmaceuticals, Five Moore Drive, PO Box 13398, Research Triangle Park, NC 27709, USA Lone H. Ottesen, GlaxoSmithKline Pharmaceuticals, Stockley Park West, 1-3 Iron Bridge Road, Uxbridge, UB11 1BT UK Alex A. Adjei, Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA Howard A. Burris III, Sarah Cannon Research Institute, 250 25th Ave North, Suite 110, Nashville, TN 37203-1632, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Background Several cancer therapies can prolong cardiac repolarization. This study assessed the potential of eribulin to affect cardiac repolarization in patients with advanced solid tumors. Methods In this Phase I, open-label, single-arm study, patients received eribulin mesylate (1.4 mg/m 2 ; Days 1 and 8 of a 21-day cycle). The primary objective was to assess the effect of eribulin on the QTcF pre- and post-infusion; QTcF and QTcNi were compared for ability to remove heart-rate dependence of the QT interval. Relationship between concentration of eribulin and ΔQTc was explored using linear mixed-effects analysis. Secondary objectives explored pharmacokinetics, safety, and tolerability. Results Twenty-six patients were enrolled. QTcNi was more effective than QTcF in correcting for heart-rate dependency of the QT interval. On Day 1, mean ΔQTcNi were ~0 at all timepoints. An apparent time-dependent increase in ΔQTc was observed: on Day 8, changes from baseline were larger and more variable, without clear relation to plasma levels of eribulin. Day 8 predose ΔQTcNi was 5 ms, post-infusion mean values ranged from 2 to 9 ms (largest mean ΔQTcNi at 6 h). No new or unexpected toxicities were reported. Conclusion Eribulin demonstrated an acceptable safety profile and a minor prolongation of QTc not expected to be of clinical concern in oncology patients. Content Type Journal Article Category PHASE I STUDIES Pages 1-10 DOI 10.1007/s10637-012-9893-8 Authors Thierry Lesimple, Clinical Research Unit, Medical Oncology Department, Comprehensive Cancer Center Eugène Marquis, CS 44229, 35042 Rennes Cedex, France Julien Edeline, Clinical Research Unit, Medical Oncology Department, Comprehensive Cancer Center Eugène Marquis, CS 44229, 35042 Rennes Cedex, France Timothy J. Carrothers, Pharsight, Sunnyvale, CA, USA Frédérique Cvitkovic, Hôpital René Huguenin, Institut Curie, Saint-Cloud, France Borje Darpo, Department of Clinical Science and Education, Section of Cardiology, Karolinska Institute, South Hospital, Stockholm, Sweden Jean-Pierre Delord, Institut Claudius Regaud, Toulouse, France Hervé Léna, Service de Pneumologie, Centre Hospitalier Universitaire, Rennes, France Nicolas Penel, Centre Oscar Lambret, Lille, France Geoff J. Edwards, Eisai Ltd, Hatfield, UK Kenneth Law, Eisai Ltd, Hatfield, UK Jantien Wanders, Eisai Ltd, Hatfield, UK Allan Kristensen, Eisai Inc, Woodcliff Lake, NJ, USA Larisa Reyderman, Eisai Inc, Woodcliff Lake, NJ, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Nasopharyngeal carcinoma (NPC) is endemic to Asia and over 40 % of NPC tissues harbor PIK3CA amplifications. This study characterized the preclinical activity of MK-2206, an oral allosteric inhibitor of AKT in 6 NPC cell lines: C666-1, HK1, HONE-1-EBV, HONE-1, CNE-2 and HNE-1. Exposure to increasing concentrations of MK-2206 resulted in over 95 % of growth inhibition in all NPC cell lines with IC 50 values in the low micromolar range. Further experiments were performed in 3 representative NPC cell lines: CNE-2 (harbor PIK3CA mutation and most sensitive to MK-2206), C666-1 (carries PIK3CA amplification), and HONE-1-EBV (least sensitive to MK-2206). MK-2206 induced G 0 /G 1 cycle arrest in all 3 cell lines, but could induce apoptosis only in CNE-2 cells. MK-2206 significantly abrogated AKT signaling in all 3 cell lines by inhibiting the activation of AKT and its downstream effectors (FKHR, GSK3β and BAD). MK-2206 also reduced mTOR signaling by reducing activation of mTOR and its downstream 4E-BP1 and p70S6 kinase. MAPK activation was observed in HONE-1 and C666-1 cells, but not in CNE-2 cells following exposure to MK-2206. The addition of MK-2206 to cisplatin (but not with paclitaxel) has a supra-additive inhibitory effect on growth in vitro. In summary, MK-2206 can inhibit growth and abrogate AKT and mTOR signaling in NPC cell lines. This agent is currently being evaluated in a phase II study in metastatic NPC. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-9 DOI 10.1007/s10637-012-9896-5 Authors Brigette B. Y. Ma, State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, Hong Kong, China Vivian W. Y. Lui, Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA Connie W. C. Hui, State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, Hong Kong, China Cecilia P. Y. Lau, State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, Hong Kong, China Chi-Hang Wong, State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, Hong Kong, China Edwin P. Hui, State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, Hong Kong, China Margaret H. Ng, Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Shatin, Hong Kong, China S. W. Tsao, Department of Anatomy, University of Hong Kong, Pokfulam, Hong Kong, China Yan Li, Infectious Disease, Oncology, Respiratory & Immunology Clinical Development, Merck Sharp and Dohme Corp, Inc, North Wales, PA, USA Anthony T. C. Chan, State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, Hong Kong, China Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Vinflunine is a novel tubulin-targeted agent that is currently indicated as a monotherapy in bladder cancer patients. The recommended dose of 320 mg/m 2 is given as an intravenous infusion once every 3 weeks. Vinflunine is metabolized through CYP3A4 and mainly eliminated via the feces. A phase I trial was designed to explore the tolerability and pharmacokinetics of vinflunine in cancer patients with ranging degrees of liver dysfunction (LD). A sequential design was used for patient accrual, with the objective of determining the maximum tolerated dose (MTD) and the recommended dose (RD) of vinflunine in 3 groups of increasing LD levels. Vinflunine and its only active metabolite 4-O-deacetylvinflunine were quantified in serial whole blood samples. PK parameters were derived and compared between LD groups and with a reference PK database. Vinflunine and 4-O-deacetylvinflunine PK parameters were not affected in any of the explored LD levels. Geometric mean values for vinflunine total clearance were 47.8, 37.5 and 45.4 L/h in the 3 groups of increasing degrees of LD, as compared to 42.5 L/h in reference patients with no LD. No relationship was found between vinflunine clearance and the presence or absence of cirrhosis, nor was it found with the presence or absence of liver metastasis or with liver-related biochemical parameters. Based on the observed tolerability profile, the recommended doses of i.v. vinflunine are 320 mg/m 2 , 250 mg/m 2 or 200 mg/m 2 for patients with increasing degrees of liver dysfunction. Content Type Journal Article Category PHASE I STUDIES Pages 1-10 DOI 10.1007/s10637-012-9878-7 Authors J. P. Delord, Institut Claudius Regaud, Toulouse, France A. Ravaud, Centre Hospitalier Universitaire, Bordeaux, France J. Bennouna, Centre René Gauducheau, Saint Herblain, France P. Fumoleau, Centre George-François Leclerc, Dijon, France S. Favrel, Institut de Recherche Pierre Fabre, Boulogne, France M. C. Pinel, Institut de Recherche Pierre Fabre, Boulogne, France P. Ferré, Institut de Recherche Pierre Fabre, Boulogne, France F. Saliba, Hôpital Paul Brousse, Villejuif, France Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    High-mannose type N-linked glycan with 6 mannosyl residues, termed "M6Gn2", displayed clear binding to the same M6Gn2, conjugated with ceramide mimetic (cer-m) and incorporated in liposome, or coated on polystyrene plates. However, the conjugate of M6Gn2-cer-m did not interact with complex-type N-linked glycan with various structures having multiple GlcNAc termini, conjugated with cer-m. The following observations indicate that hamster embryonic fibroblast NIL-2 K cells display homotypic autoadhesion, mediated through the self-recognition capability of high-mannose type glycans expressed on these cells: (i) NIL-2 K cells display clear binding to lectins capable of binding to high-mannose type glycans ( e.g. , ConA), but not to other lectins capable of binding to other carbohydrates ( e.g. GS-II). (ii) NIL-2 K cells adhere strongly to plates coated with M6Gn2-cer-m, but not to plates coated with complex-type N-linked glycans having multiple GlcNAc termini, conjugated with cer-m; (iii) degree of NIL-2 K cell adhesion to plates coated with M6Gn2-cer-m showed a clear dose-dependence on the amount of M6Gn2-cer-m; and (iv) the degree of NIL-2 K adhesion to plates coated with M6Gn2-cer-m was inhibited in a dose-dependent manner by α1,4-L-mannonolactone, the specific inhibitor in high-mannose type glycans addition. These data indicate that adhesion of NIL-2 K is mediated by self-aggregation of high mannose type glycan. Further studies are to be addressed on auto-adhesion of other types of cells based on self interaction of high mannose type glycans. Content Type Journal Article Pages 1-12 DOI 10.1007/s10719-012-9449-3 Authors Seon-Joo Yoon, Division of Biomembrane Research, Pacific Northwest Research Institute, and Department of Global Health, University of Washington, Seattle, WA 98122, USA Natalia Utkina, Division of Biomembrane Research, Pacific Northwest Research Institute, and Department of Global Health, University of Washington, Seattle, WA 98122, USA Martin Sadilek, Depart of Chemistry, University of Washington, Seattle, WA 98195, USA Hirokazu Yagi, Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori 3-1, Mizuho-ku, Nagoya, 467-8603 Japan Koichi Kato, Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori 3-1, Mizuho-ku, Nagoya, 467-8603 Japan Sen-itiroh Hakomori, Division of Biomembrane Research, Pacific Northwest Research Institute, and Department of Global Health, University of Washington, Seattle, WA 98122, USA Journal Glycoconjugate Journal Online ISSN 1573-4986 Print ISSN 0282-0080

Description:    The ethylene glycol-1,4-dioxane system is studied by means of differential scanning calorimetry over a wide range of temperatures (−90 to 25°C) and is found to be a simple eutectic with the eutectic point at 10 mol % of dioxane (−16.5°C). Unlike a water-dioxane system, in which the clathrate with dioxane: H 2 O = 1: 34 ratio is formed, the observed phase diagram showed no evidence of clathrate formation, due presumably to its hydrogen bond geometry and the intermolecular interaction properties of ethylene glycol. Content Type Journal Article Category Short Communications Pages 1745-1746 DOI 10.1134/S0036024412110234 Authors M. N. Rodnikova, Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Moscow, 119991 Russia I. A. Solonina, Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Moscow, 119991 Russia M. R. Kiselev, Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Moscow, 119071 Russia S. V. Makaev, Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Moscow, 119991 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 11

Description:    The solubility of atmospheric oxygen in solutions of surfactants of different natures at 293 K and pH 8 is determined by gas chromatography. It is found that additives of nonionic surfactants decrease the oxygen content in the solution in the premicellar region and increase its solubility in the micellar region. It is shown that, for anionic surfactants, a decrease in the solubility of O 2 is observed over the entire concentration range. Content Type Journal Article Category Short Communications Pages 1753-1755 DOI 10.1134/S0036024412110088 Authors G. V. Chistyakova, Krestov Institute of Solution Chemistry, Russian Academy of Sciences, Ivanovo, 153045 Russia S. A. Koksharov, Krestov Institute of Solution Chemistry, Russian Academy of Sciences, Ivanovo, 153045 Russia T. V. Vladimirova, Ivenergo, Ivanovo, 153326 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 11

Description:    It was shown that after partial dehydration occurs a simultaneous condensation of four mol of initial monomer Gd(NO 3 ) 3 · 6H 2 O into a tetramer Gd 4 O 4 (NO 3 ) 4 . The heterocycle containing 4 gadolinium atoms gradually loses N 2 O 5 and, through the formation of unstable oxynitrates, is transformed into Gd 2 O 3 . The interatomic distances and angles were calculated using the molecular mechanics method. The comparison of the potential energies of consecutive oxyphosphates permitted an evaluation of their stability. The models of intermediate oxynitrates represent a reasonably good approximation to the real structures and a proper interpretation of experimental data. Content Type Journal Article Category Chemical Kinetics and Catalysis Pages 1659-1663 DOI 10.1134/S0036024412110180 Authors P. P. Melnikov, Federal University of Mato Grosso do Sul/UFMS, Caixa Postal 549, Campo Grande/MS, Brazil V. A. Nascimento, Federal University of Mato Grosso do Sul/UFMS, Caixa Postal 549, Campo Grande/MS, Brazil L. Z. Zanoni Consolo, Federal University of Mato Grosso do Sul/UFMS, Caixa Postal 549, Campo Grande/MS, Brazil Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 11

Description:    A dimensionless complex containing the surface free energy of a crystal-liquid interface γ, and the entropy jump, temperature, and density of a crystal phase is described using the phenomenology of thermodynamic similarity; this complex remains constant at the melting line. It is demonstrated that the complex refines the result obtained by Skripov and Faizullin in [6] and enables us to estimate the temperature dependence of γ. Our calculations show that the surface free energy of the crystal-liquid interface of normally melting compounds is a monotonically increasing function of temperature. Content Type Journal Article Category Short Communications Pages 1763-1765 DOI 10.1134/S0036024412110040 Authors V. G. Baidakov, Institute of Thermal Physics, Ural Branch, Russian Academy of Sciences, Yekaterinburg, 620016 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 11

Description:    Thermodynamic parameters are determined for the adsorption of vapors of hydrocarbons and polar compounds of different structure on carbon adsorbent modified by a monomolecular layer of heptakis (2,3,6-tri- O -benzoyl)-β-cyclodextrin. The effect of the structure and polarity of organic compounds on adsorption onto an adsorbent support with a chiral macrocyclic modifier are considered. Content Type Journal Article Category Short Communications Pages 1769-1772 DOI 10.1134/S0036024412110155 Authors K. A. Kopytin, Samara State University, Samara, 443011 Russia S. Yu. Kudryashov, Samara State University, Samara, 443011 Russia N. G. Gerasimova, Samara State University, Samara, 443011 Russia L. A. Onuchak, Samara State University, Samara, 443011 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 11

Description:    A thermodynamic variation of the Lindemann criterion for the vaporization of metals is proposed. It is shown that the critical amplitude of vibrations of atoms at the boiling point averages 1.42 bond lengths. Close values of interatomic distances result from the Vinet universal equation for the atomization of metals under the action of high temperatures (1.48) and negative pressures (1.50). The last value corresponds to the Van der Waals distances between metal atoms. Content Type Journal Article Category Short Communications Pages 1759-1762 DOI 10.1134/S0036024412110052 Authors S. S. Batsanov, Institute of Structural Macrokinetics and Problems of Materials Science, Russian Academy of Sciences, Chernogolovka, Moscow oblast, 142432 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 11

Description:    Samples of composite nanomaterials obtained by the thermal treatment of mixtures of MoO 3 nano-dispersed powder and ultrafine powder of Mo with precipitate from removing iron from groundwater are studied by means of X-ray diffraction and infrared spectroscopy. The structure of these samples (phase composition, average crystallite size, microdistortions (microstresses) of their crystal lattices, and certain texture parameters) are determined. It is suggested that under certain conditions, shells from the nanoparticles of Mo and/or MoO 3 are formed on the surface of sediment particles, preventing the identification of iron-containing phases. Estimates are made of the sorption activity of some materials with respect to carbon monoxide (CO). Content Type Journal Article Category Physical Chemistry of Nanoclusters and Nanomaterials Pages 1689-1696 DOI 10.1134/S0036024412110210 Authors L. Yu. Novoselova, Institute of Petroleum Chemistry, Siberian Branch, Russian Academy of Sciences, Tomsk, 634021 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 11

Description:    A table for determining the first derivatives of thermodynamic parameters is proposed. The table differs from the familiar Suvorov table in that the five dimension parameters are replaced with four dimensionless thermodynamic parameters. Content Type Journal Article Category Short Communications Pages 1747-1750 DOI 10.1134/S003602441211009X Authors V. P. Dobrodeev, Rybinsk State Aviation Technological Academy, Rybinsk, 152934 Russia N. A. Kalyaeva, Rybinsk State Aviation Technological Academy, Rybinsk, 152934 Russia A. V. Dobrodeev, Rybinsk State Aviation Technological Academy, Rybinsk, 152934 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 11

Description:    The conjugated diffusion transport of amino acid and mineral salt through a profiled sulfo group cation exchange membrane that simulates the extraction of amino acid from wash waters of microbiological production containing mineral components not used in synthesis is studied. The competitive nature of the conjugation of flows resulting in a decrease in the rate of the mass transfer of components and their separation factor is established from a comparative analysis of experimental data on the diffusion transfer of phenylalanine and sodium chloride in the form of hydrogen from individual and mixed solutions through a profiled sulfo group cation exchange membrane. The range of concentrations and the ratio of components in solution corresponding to the effective separation of phenylalanine and sodium chloride are determined. Content Type Journal Article Category Physical Chemistry of Separation Processes: Chromatography Pages 1726-1731 DOI 10.1134/S0036024412110271 Authors V. I. Vasil’eva, Voronezh State University, Voronezh, 394006 Russia E. A. Vorob’eva, Voronezh State University, Voronezh, 394006 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 11

Description:    Human alpha-1-antitrypsin (α1AT) is a glycoprotein with protease inhibitor activity protecting tissues from degradation. Patients with inherited α1AT deficiency are treated with native α1AT (nAT) purified from human plasma. In the present study, recombinant α1AT (rAT) was produced in Chinese hamster ovary (CHO) cells and their glycosylation patterns, inhibitory activity and in vivo half-life were compared with those of nAT. A peptide mapping analysis employing a deglycosylation reaction confirmed full occupancy of all three glycosylation sites and the equivalency of rAT and nAT in terms of the protein level. N -glycan profiles revealed that rAT contained 10 glycan structures ranging from bi-antennary to tetra-antennary complex-type glycans while nAT displayed six peaks comprising majorly bi-antennary glycans and a small portion of tri-antennary glycans. In addition, most of the rAT glycans were shown to have only core α(1 - 6)-fucose without terminal fucosylation, whereas only minor portions of the nAT glycans contained core or Lewis X-type fucose. As expected, all sialylated glycans of rAT were found to have α(2 - 3)-linked sialic acids, which was in sharp contrast to those of nAT, which had mostly α(2 - 6)-linked sialic acids. However, the degree of sialylation of rAT was comparable to that of nAT, which was also supported by an isoelectric focusing gel analysis. Despite the differences in the glycosylation patterns, both α1ATs showed nearly equivalent inhibitory activity in enzyme assays and serum half-lives in a pharmacokinetic experiment. These results suggest that rAT produced in CHO cells would be a good alternative to nAT derived from human plasma. Content Type Journal Article Pages 1-11 DOI 10.1007/s10719-012-9453-7 Authors Kyung Jin Lee, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 305-806 Korea Sang Mee Lee, Alteogen Inc., Bioventure town, Daejeon, 305-812 Korea Jin Young Gil, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 305-806 Korea Ohsuk Kwon, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 305-806 Korea Jin Young Kim, Korea Basic Science Institute, Ochang-eup, Cheongwon-gun, Chungbuk 363-883, Korea Soon Jae Park, Alteogen Inc., Bioventure town, Daejeon, 305-812 Korea Hye-Shin Chung, Alteogen Inc., Bioventure town, Daejeon, 305-812 Korea Doo-Byoung Oh, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 305-806 Korea Journal Glycoconjugate Journal Online ISSN 1573-4986 Print ISSN 0282-0080

Description:    As one of several biologically active compounds in milk, glycoproteins have been indicated to be involved in the protection of newborns from bacterial infection. As much of the physical and immune development of the tammar wallaby ( Macropus eugenii ) young occurs during the early phases of lactation and not in utero , the tammar is a model species for the characterization of potential developmental support agents provided by maternal milk. In the present study, the N - and O -linked glycans from tammar wallaby milk glycoproteins from six individuals at different lactation time points were subjected to glycomics analyses using porous graphitized carbon liquid chromatography electrospray ionization mass spectrometry. Structural characterization identified a diverse range of glycan structures on wallaby milk glycoproteins including sialylated, sulphated, core fucosylated and O -fucosylated structures. 30 % of N -linked structures contained a core (α1-6) fucose. Several of these structures may play roles in development, and exhibit statistically significant temporal changes over the lactation period. The N -glycome was found to contain structures with NeuGc residues, while in contrast the O -glycome did not. O -fucosylated structures were identified in the early stages of lactation indicating a potential role in the early stages of development of the pouch young. Overall the results suggest that wallaby milk contains structures known to have developmental and immunological significance in human milk and reproduction in other animals, highlighting the importance of glycoproteins in milk. Content Type Journal Article Pages 1-14 DOI 10.1007/s10719-012-9452-8 Authors Katherine Wongtrakul-Kish, Biomolecular Frontiers Research Centre, Department of Chemistry and Biomolecular Sciences, Macquarie University, Building E8C Room 307, North Ryde, NSW 2109, Australia Daniel Kolarich, Biomolecular Frontiers Research Centre, Department of Chemistry and Biomolecular Sciences, Macquarie University, Building E8C Room 307, North Ryde, NSW 2109, Australia Dana Pascovici, Australian Proteome Analysis Facility, Macquarie University, North Ryde, NSW 2109, Australia Janice L. Joss, Department of Biological Sciences, Macquarie University, North Ryde, NSW 2109, Australia Elizabeth Deane, Department of Biological Sciences, Macquarie University, North Ryde, NSW 2109, Australia Nicolle H. Packer, Biomolecular Frontiers Research Centre, Department of Chemistry and Biomolecular Sciences, Macquarie University, Building E8C Room 307, North Ryde, NSW 2109, Australia Journal Glycoconjugate Journal Online ISSN 1573-4986 Print ISSN 0282-0080

Description:    Chaetoglobosin K (ChK) is a natural product that inhibits anchorage-dependent and anchorage-independent growth of ras -transformed cells, prevents tumor-promoter disruption of cell-cell communication, and reduces Akt activation in tumorigenic cells. This study demonstrates how ChK modulates the JNK pathway in ras -transformed and human lung carcinoma cells and investigates regulatory mechanisms controlling ChK’s effect on the Akt and JNK signaling pathways. Human lung carcinoma and ras -transformed epithelial cell lines treated with ChK or vehicle for varying times were assayed for cell growth or extracted for total proteins for western blot analysis using phosphorylation site-specific antibodies to monitor changes in activation of JNK, Akt, and other signaling enzymes. Results show that ChK inhibited both Akt and JNK phosphorylation at key activation sites in ras -transformed cells as well as human lung carcinoma cells. Downstream effectors of both kinases were accordingly affected. Direct upstream kinases of JNK were not affected by ChK. Wortmannin and LY294002, two PI3 kinase inhibitors, inhibited Akt but not JNK phosphorylation in ras -transformed cells. This report establishes the dual inhibitory effect of ChK on both the Akt and JNK signaling pathways in ras -transformed epithelial and human carcinoma cells. The unique effect of ChK on these two key pathways involved in carcinogenesis earmarks ChK for further studies to determine its molecular target(s) and in vivo anti-tumor potential. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-10 DOI 10.1007/s10637-012-9883-x Authors Amna Ali, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Mercer University, 3001 Mercer University Drive, Atlanta, GA 30341, USA Tatyana S. Sidorova, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Mercer University, 3001 Mercer University Drive, Atlanta, GA 30341, USA Diane F. Matesic, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Mercer University, 3001 Mercer University Drive, Atlanta, GA 30341, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    This phase I, open-label, dose-escalation study assessed the maximum-tolerated dose, safety, pharmacokinetics, and preliminary antitumor activity of pazopanib plus lapatinib combination therapy in patients with solid tumors. Patients were to take pazopanib and lapatinib orally once daily in a fasting condition. During the escalation phase, pazopanib and lapatinib doses were escalated in serial patient cohorts, and a limited blood sampling scheme was applied for pharmacokinetic evaluation. In the expansion phase, potential pharmacokinetic interaction between pazopanib and lapatinib was evaluated more extensively. Seventy-five patients were treated. Multiple dosing levels were studied, combining pazopanib up to 800 mg/day with lapatinib up to 1,500 mg/day. Dose-limiting toxicities observed included grade 3 neutropenia, fatigue, asymptomatic decline in left ventricular ejection fraction, diarrhea, and liver enzyme elevations. The most common drug-related adverse events were diarrhea, nausea, anorexia, fatigue, vomiting, rash, hair depigmentation, and hypertension. The dose recommended for further evaluation was pazopanib 800 mg plus lapatinib 1,500 mg (paz-800/lap-1500). No clinically significant drug-drug interaction was observed at the paz-400/lap-1000 level. However, at paz-800/lap-1500, an increase in both the AUC 0-t and C max of pazopanib was observed. Four partial responses were observed in patients with renal cancer ( n  = 2), giant-cell tumor of the bone ( n  = 1), and thyroid cancer ( n  = 1). Stable disease for ≥18 weeks was seen in 12 patients. Pazopanib and lapatinib can be administered in combination at their respective single-agent doses with an acceptable safety profile. Further evaluation of the combination will be pursued, exploring both paz-800/lap-1500 and paz-400/lap-1000. Content Type Journal Article Category PHASE I STUDIES Pages 1-9 DOI 10.1007/s10637-012-9885-8 Authors Maja J. A. de Jonge, Department of Medical Oncology, Erasmus University Medical Center/Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands Paul Hamberg, Erasmus University Medical Center/Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands Jaap Verweij, Erasmus University Medical Center/Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands Shawna Savage, Duke Medical Center, 2100 Erwin Road, Durham, NC 27705, USA A. Benjamin Suttle, GlaxoSmithKline, Five Moore Drive, PO Box 13398, Research Triangle Park, NC 27709, USA Jeffrey Hodge, GlaxoSmithKline, Five Moore Drive, PO Box 13398, Research Triangle Park, NC 27709, USA Thangam Arumugham, GlaxoSmithKline, Five Moore Drive, PO Box 13398, Research Triangle Park, NC 27709, USA Lini N. Pandite, GlaxoSmithKline, Five Moore Drive, PO Box 13398, Research Triangle Park, NC 27709, USA Herbert I. Hurwitz, Duke Medical Center, 2100 Erwin Road, Durham, NC 27705, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Targeting tumor vasculature represents a rational strategy for controlling cancer. (Z)-(+/−)-2-(1-benzylindol-3-ylmethylene)-1-azabicyclo[2.2.2]octan-3-ol (denoted VJ115) is a novel chemical entity that inhibits the enzyme ENOX1, a NADH oxidase. Genetic and small molecule inhibition of ENOX1 inhibits endothelial cell tubule formation and tumor-mediated neo-angiogenesis. Inhibition of ENOX1 radiosensitizes tumor vasculature, a consequence of enhanced apoptosis. However, the molecular mechanisms underlying these observations are not well understood. Herein, we mechanistically link ENOX1-mediated regulation of cellular NADH concentrations with proteomics profiling of endothelial cell protein expression following exposure to VJ115. Pathway Studios network analysis of potential effector molecules identified by the proteomics profiling indicated that a VJ115 exposure capable of altering intracellular NADH concentrations impacted proteins involved in cytoskeletal reorganization. The analysis was validated using RT-PCR and immunoblotting of selected proteins. RNAi knockdown of ENOX1 was shown to suppress expression of stathmin and lamin A/C, proteins identified by the proteomics analysis to be suppressed upon VJ115 exposure. These data support the hypothesis that VJ115 inhibition of ENOX1 can impact expression of proteins involved in cytoskeletal reorganization and support a hypothesis in which ENOX1 activity links elevated cellular NADH concentrations with cytoskeletal reorganization and angiogenesis. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-10 DOI 10.1007/s10637-012-9884-9 Authors Amudhan Venkateswaran, Department of Radiation Oncology, Vanderbilt University, Nashville, TN 37232, USA David B. Friedman, Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA Alexandra J. Walsh, Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA Melissa C. Skala, Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA Soumya Sasi, Department of Radiation Oncology, Vanderbilt University, Nashville, TN 37232, USA Girish Rachakonda, Department of Radiation Oncology, Vanderbilt University, Nashville, TN 37232, USA Peter A. Crooks, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA Michael L. Freeman, Department of Radiation Oncology, Vanderbilt University, Nashville, TN 37232, USA Konjeti R. Sekhar, Department of Radiation Oncology, Vanderbilt University, Nashville, TN 37232, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description: Glycosylation effects on cancer development Content Type Journal Article Pages 1-2 DOI 10.1007/s10719-012-9448-4 Authors Sen-itiroh Hakomori, Division of Biomembrane Research, Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122, USA Richard D. Cummings, Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA Journal Glycoconjugate Journal Online ISSN 1573-4986 Print ISSN 0282-0080

Description:    Hepatocellular carcinoma (HCC) is the most common liver malignancy still demanding for novel therapeutic options. Since the ion channel inhibitor TRAM-34 (1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole) was shown to block growth in various cancer cells, we investigated anti-tumor effects of TRAM-34 in human HCC cell lines. We found that TRAM-34 reduced HCC cell proliferation without induction of apoptosis. This was due to a decreased mRNA expression of estrogen receptor alpha (ESR1) and a reduced activation of NF-kappaB, which both are implicated in the development of HCC. Therefore, TRAM-34 might represent a novel therapeutic target for the treatment of HCC. Content Type Journal Article Category Short Report Pages 1-6 DOI 10.1007/s10637-012-9879-6 Authors Christian Freise, Department of Gastroenterology, Infectiology and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany Martin Ruehl, Department of Gastroenterology, Infectiology and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany Daniel Seehofer, Department of General, Visceral and Transplantation Surgery, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany Joachim Hoyer, Department of Nephrology, Philipps-Universität Marburg, Marburg, Germany Rajan Somasundaram, Department of Gastroenterology, Infectiology and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Purpose Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G. Experimental Design Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m 2 over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured. Results Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m 2 (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome. Conclusions This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure. Content Type Journal Article Category PHASE I STUDIES Pages 1-11 DOI 10.1007/s10637-012-9863-1 Authors Amir Mortazavi, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA Yonghua Ling, Pharmacoanalytical Shared Resources, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH 43210, USA Ludmila Katherine Martin, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA Lai Wei, Center for Biostatistics, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH 43210, USA Mitch A. Phelps, Division of Pharmaceutics, College of Pharmacy, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH 43210, USA Zhongfa Liu, Division of Pharmaceutics, College of Pharmacy, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH 43210, USA Erica J. Harper, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA S. Percy Ivy, Cancer Therapeutics Evaluation Program, National Cancer Institute, Rockville, MD 20852, USA Xin Wu, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA Bing-Sen Zhou, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA Xiyong Liu, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA Deidre Deam, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA J. Paul Monk, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA William J. Hicks, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA Yun Yen, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA Gregory A. Otterson, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA Michael R. Grever, Division of Hematology, Department of Internal Medicine, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH 43210, USA Tanios Bekaii-Saab, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    We have analyzed the structures of glycosphingolipids and intracellular free glycans in human cancers. In our previous study, trace amounts of free N -acetylneuraminic acid (Neu5Ac)-containing complex-type N -glycans with a single GlcNAc at each reducing terminus (Gn1 type) was found to accumulate intracellularly in colorectal cancers, but were undetectable in most normal colorectal epithelial cells. Here, we used cancer glycomic analyses to reveal that substantial amounts of free Neu5Ac-containing complex-type N -glycans, almost all of which were α2,6-Neu5Ac-linked, accumulated in the pancreatic cancer cells from three out of five patients, but were undetectable in normal pancreatic cells from all five cases. These molecular species were mostly composed of five kinds of glycans having a sequence Neu5Ac-Gal-GlcNAc-Man-Man-GlcNAc and one with the following sequence Neu5Ac-Gal-GlcNAc-Man-(Man-)Man-GlcNAc. The most abundant glycan was Neu5Acα2-6Galβ1-4GlcNAcβ1-2Manα1-3Manβ1-4GlcNAc, followed by Neu5Acα2-6Galβ1-4GlcNAcβ1-2Manα1-6Manβ1-4GlcNAc. This is the first study to show unequivocal evidence for the occurrence of free Neu5Ac-linked N -glycans in human cancer tissues. Our findings suggest that free Neu5Ac-linked glycans may serve as a useful tumor marker. Content Type Journal Article Pages 1-10 DOI 10.1007/s10719-012-9435-9 Authors Masahiko Yabu, Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka, 537-8511 Japan Hiroaki Korekane, Systems Glycobiology Research Group, Chemical Biology Department, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan Hidenori Takahashi, Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka, 537-8511 Japan Hiroaki Ohigashi, Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka, 537-8511 Japan Osamu Ishikawa, Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka, 537-8511 Japan Yasuhide Miyamoto, Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka, 537-8511 Japan Journal Glycoconjugate Journal Online ISSN 1573-4986 Print ISSN 0282-0080

Description:    Purpose Population pharmacokinetics (PK) of sepantronium bromide (YM155) was characterized in patients with non-small cell lung cancer, hormone refractory prostate cancer, or unresectable stage III or IV melanoma and enrolled in one of three phase 2 studies conducted in Europe or the U.S. Method Sepantronium was administered as a continuous intravenous infusion (CIVI) at 4.8 mg/m 2 /day over 7 days every 21 days. Population PK analysis was performed using a linear one-compartment model involving total body clearance (CL) and volume of distribution with an inter-individual random effect on CL and a proportional residual errors to describe 578 plasma sepantronium concentrations obtained from a total of 96 patients by NONMEM Version VI. The first-order conditional estimation method with interaction was applied. Results The one-compartment model with one random effect on CL and two different proportional error models provided an adequate description of the data. Creatinine clearance (CL CR ), cancer type, and alanine aminotransferase (ALT) were recognized as significant covariates of CL. CL CR was the most influential covariate on sepantronium exposure and predicted to contribute to a 25 % decrease in CL for patients with moderately impaired renal function (CL CR  = 40 mL/min) compared to patients with normal CL CR . Cancer type and ALT had a smaller but nonetheless significant contribution. Other patient characteristics such as age, gender, and race were not considered as significant covariates of CL. Conclusions The results provide the important information for optimizing the therapeutic efficacy and minimizing the toxicity for sepantronium in cancer therapy. Content Type Journal Article Category PHASE II STUDIES Pages 1-9 DOI 10.1007/s10637-012-9867-x Authors Yumiko Aoyama, Clinical Pharmacology, Astellas Pharma Inc., 3-17-1, Hasune, Itabashi-ku, Tokyo, 174-8612 Japan Atsunori Kaibara, Clinical Pharmacology, Astellas Pharma Inc., 3-17-1, Hasune, Itabashi-ku, Tokyo, 174-8612 Japan Akitsugu Takada, Clinical Pharmacology, Astellas Pharma Inc., 3-17-1, Hasune, Itabashi-ku, Tokyo, 174-8612 Japan Tetsuya Nishimura, Clinical Pharmacology, Astellas Pharma Inc., 3-17-1, Hasune, Itabashi-ku, Tokyo, 174-8612 Japan Masataka Katashima, Clinical Pharmacology, Astellas Pharma Inc., 3-17-1, Hasune, Itabashi-ku, Tokyo, 174-8612 Japan Taiji Sawamoto, Clinical Pharmacology, Astellas Pharma Inc., 3-17-1, Hasune, Itabashi-ku, Tokyo, 174-8612 Japan Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Sulfatides, 3- O -sulfogalactosylceramides, are known to have multifunctional properties. These molecules are distributed in various tissues of mammals, where they are synthesized from galactosylceramides by sulfation at C3 of the galactosyl residue. Although this reaction is specifically catalyzed by cerebroside sulfotransferase (CST), the mechanisms underlying the transcriptional regulation of this enzyme are not understood. With respect to this issue, we previously found potential sequences of peroxisome proliferator-activated receptor (PPAR) response element on upstream regions of the mouse CST gene and presumed the possible regulation by the nuclear receptor PPARα. To confirm this hypothesis, we treated wild-type and Ppara -null mice with the specific PPARα agonist fenofibrate and examined the amounts of sulfatides and CST gene expression in various tissues. Fenofibrate treatment increased sulfatides and CST mRNA levels in the kidney, heart, liver, and small intestine in a PPARα-dependent manner. However, these effects of fenofibrate were absent in the brain or colon. Fenofibrate treatment did not affect the mRNA level of arylsulfatase A, which is the key enzyme for catalyzing desulfation of sulfatides, in any of these six tissues. Analyses of the DNA-binding activity and conventional gene expression targets of PPARα has demonstrated that fenofibrate treatment activated PPARα in the kidney, heart, liver, and small intestine but did not affect the brain or colon. These findings suggest that PPARα activation induces CST gene expression and enhances sulfatide synthesis in mice, which suggests that PPARα is a possible transcriptional regulator for the mouse CST gene. Content Type Journal Article Pages 1-8 DOI 10.1007/s10719-012-9454-6 Authors Takero Nakajima, Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan Yuji Kamijo, Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan Huang Yuzhe, Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan Takefumi Kimura, Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan Naoki Tanaka, Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan Eiko Sugiyama, Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan Kozo Nakamura, Department of Bioscience and Biotechnology, Faculty of Agriculture, Shinshu University, Minami-Minowa, Kami-Ina, Nagano, Japan Mamoru Kyogashima, Division of Microbiology and Molecular Cell Biology, Nihon Pharmaceutical University, Ina, Kita-Adachi, Saitama, Japan Atsushi Hara, Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan Toshifumi Aoyama, Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan Journal Glycoconjugate Journal Online ISSN 1573-4986 Print ISSN 0282-0080

Description:    The aim of this study was to investigate the effect of lapatinib, a selective inhibitor of EGFR/HER2 tyrosine kinases, on pancreatic cancer cell lines both alone and in combination with chemotherapy. Two cell lines, BxPc-3 and HPAC, displayed the greatest sensitivity to lapatinib (IC 50  〈 2 μM). Lapatinib also demonstrated some activity in three K-Ras mutated pancreatic cancer cell lines which displayed resistance to erlotinib. Drug effect/combination index (CI) isobologram analysis was used to study the interactions of lapatinib with gemcitabine, cisplatin and 5’deoxy-5’fluorouridine. Concentration-dependent anti-proliferative effects of lapatinib in combination with chemotherapy were observed. To evaluate the potential effect of lapatinib in pancreatic cancer tumours, and to identify a subset of patient most likely to benefit from lapatinib, expression of EGFR and HER2 were investigated in 72 pancreatic cancer tumour specimens by immunohistochemistry. HER2 membrane expression was observed in only 1 % of cases, whereas 44 % of pancreatic tumours expressed EGFR. Based on our in vitro results, lapatinib may provide clinical benefit in EGFR positive pancreatic ductal adenocarcinoma. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-9 DOI 10.1007/s10637-012-9891-x Authors Naomi Walsh, Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland Susan Kennedy, St. Vincent’s University Hospital, Dublin, Ireland AnneMarie Larkin, Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland Brendan Corkery, Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland Lorraine O’Driscoll, Molecular Therapeutics for Cancer Ireland, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland Martin Clynes, Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland John Crown, Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland Norma O’Donovan, Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Background Hepatocellular carcinoma (HCC) cells are auxotrophic for arginine, depletion of which leads to tumour regression. The current study evaluated safety, pharmacokinetics (PK)/ pharmacodynamics (PD) parameters, and potential anti-tumor activity of pegylated recombinant human arginase 1 (peg-rhArg1) in advanced HCC patients. Methods Eligibility criteria included advanced HCC with measurable lesions, Child-Pugh A or B, and adequate organ function. Initial single IV bolus was followed by weekly doses of peg-rhArgI escalated from 500 U/kg to 2500 U/kg in a 3 + 3 design. Results Fifteen patients were enrolled at weekly doses of 500 U/kg ( n  = 3), 1000 U/kg ( n  = 3), 1600 U/kg ( n  = 3) and 2500 U/kg ( n  = 6). The median age was 57 years (33–74); 87% were hepatitis B carriers and 47% had prior systemic treatment. The most commonly reported drug-related non-haematological adverse events (AEs) were diarrhea (13.3%), abdominal discomfort (6.7%) and nausea (6.7%). No drug-related haematological AEs were seen. Only 1 of the six patients that received 2500U/kg peg-rhArg1 experienced DLT (grade 4 bilirubin elevation) and thus the maximum tolerated dose was 2500 U/kg. PK and PD analysis indicated that peg-rhArg1 was efficacious in inducing arginine depletion in a dose-dependent manner. Adequate arginine depletion dose was achieved in the 1,600–2,500 U/kg range and therefore the optimal biological dose was at 1600 U/kg, which was chosen as the recommended dose. The best response was stable disease for 〉8 weeks in 26.7% of the enrolled patients. Conclusion Peg-rhArg1 has manageable safety profile and preliminary evidence of activity in advanced HCC patients. Content Type Journal Article Category PHASE I STUDIES Pages 1-9 DOI 10.1007/s10637-012-9807-9 Authors Thomas Yau, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China P. N. Cheng, Bio-Cancer Treatment International Limited, Rm 511-513, 5/F, Bio-Informatics Centre, 2 Science Park West Avenue, Hong Kong Science Park, Shatin, NT, Hong Kong Pierre Chan, Department of Medicine, Ruttonjee Hospital, 266 Queen’s Road East, Wan Chai, Hong Kong William Chan, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong, China Li Chen, Bio-Cancer Treatment International Limited, Rm 511-513, 5/F, Bio-Informatics Centre, 2 Science Park West Avenue, Hong Kong Science Park, Shatin, NT, Hong Kong Jimmy Yuen, Hong Kong Sanatorium & Hospital, 2 Village Road, Happy Valley, Hong Kong Roberta Pang, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong, China S. T. Fan, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong, China Ronnie T. Poon, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong, China Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Background This phase I study evaluated the safety, tolerability and preliminary efficacy of sorafenib combined with vorinostat in patients with solid tumors. Patients and methods Patients were treated with sorafenib 400 mg po bid daily and vorinostat 200–400 mg po days 1–14 of a 21 day cycle to establish the recommended phase II dose (RP2D). The tolerability and efficacy of the RP2D was further tested in two cohorts of 6–12 patients each with advanced RCC and NSCLC. Results 17 patients were treated in the dose escalation phase that established the RP2D at sorafenib 400 mg po bid daily, vorinostat 300 mg po days 1–14. Dose limiting toxicities (DLT) included intolerable grade 2 hand-foot syndrome and multiple grade 1 toxicities causing dose interruption for more than 14 days. Despite good tolerance in the all-comers population, the RP2D was poorly tolerated in the RCC and NSCLC cohorts with the majority being unable to finish 2 full cycles of therapy. Although there were no confirmed responses, 1 patient each with NSCLC adenocarcinoma and renal sarcoma had unconfirmed partial responses and 5 of 8 patients with RCC having durable minor responses (11–26 %), including 2 who were on treatment for nearly a year. Conclusions Although tolerable in other tumor types, sorafenib 400 mg po bid with vorinostat 300 mg po daily days 1–14 of a 21-day cycle is not tolerable without dose reductions/delays in RCC and NSCLC patients. These patients may require lower doses than the RP2D explored within this study. No confirmed responses were seen but minor responses particularly in RCC were observed. Content Type Journal Article Category PHASE I STUDIES Pages 1-11 DOI 10.1007/s10637-012-9812-z Authors A. Dasari, University of Colorado Cancer Center, Aurora, CO, USA L. Gore, University of Colorado Cancer Center, Aurora, CO, USA W. A. Messersmith, University of Colorado Cancer Center, Aurora, CO, USA S. Diab, University of Colorado Cancer Center, Aurora, CO, USA A. Jimeno, University of Colorado Cancer Center, Aurora, CO, USA C. D. Weekes, University of Colorado Cancer Center, Aurora, CO, USA K. D. Lewis, University of Colorado Cancer Center, Aurora, CO, USA H. A. Drabkin, Medical University of South Carolina, Charleston, SC, USA T. W. Flaig, University of Colorado Cancer Center, Aurora, CO, USA D. R. Camidge, University of Colorado Cancer Center, Aurora, CO, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Effective inhibition of BCR-ABL tyrosine kinase activity with Imatinib represents a breakthrough in the treatment of patients with chronic myeloid leukemia (CML). However, more than 30 % of patients with CML in chronic phase do not respond adequately to Imatinib and the drug seems not to affect the quiescent pool of BCR-ABL positive leukemic stem and progenitor cells. Therefore, despite encouraging clinical results, Imatinib can still not be considered a curative treatment option in CML. We recently reported downregulation of eukaryotic initiation factor 5A (eIF5A) in Imatinib treated K562 cells. Furthermore, the inhibition of eIF5A by siRNA in combination with Imatinib has been shown to exert synergistic cytotoxic effects on BCR-ABL positive cell lines. Based on the structure of known deoxyhypusine synthase (DHS) inhibitors such as CNI-1493, a drug design approach was applied to develop potential compounds targeting DHS. Here we report the biological evaluation of selected novel (DHSI-15) as compared to established (CNI-1493, deoxyspergualin) DHS inhibitors. We show that upon the compounds tested, DHSI-15 and deoxyspergualin exert strongest antiproliferative effects on BCR-ABL cells including Imatinib resistant mutants. However, this effect did not seem to be restricted to BCR-ABL positive cell lines or primary cells. Both compounds are able to induce apoptosis/necrosis during long term incubation of BCR-ABL positive BA/F3 derivates. Pharmacological synergism can be observed for deoxyspergualin and Imatinib, but not for DHSI-15 and Imatinib. Finally we show that deoxyspergualin is able to inhibit proliferation of CD34+ progenitor cells from CML patients. We conclude that inhibition of deoxyhypusine synthase (DHS) can be supportive for the anti-proliferative treatment of leukemia and merits further investigation including other cancers. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-10 DOI 10.1007/s10637-012-9810-1 Authors Patrick Ziegler, Klinik für Onkologie, Hämatologie und Stammzelltransplantation, Universitätsklinikum der RWTH, Aachen University, Aachen, Germany Tuhama Chahoud, Department of Oncology, Haematology and Bone marrow transplantation with section Pneumology, Hubertus Wald-Tumor Zentrum (UCCH), University Hospital Eppendorf (UKE), Hamburg, Germany Thomas Wilhelm, Department of Oncology, Haematology and Bone marrow transplantation with section Pneumology, Hubertus Wald-Tumor Zentrum (UCCH), University Hospital Eppendorf (UKE), Hamburg, Germany Nora Pällman, Department of Oncology, Haematology and Bone marrow transplantation with section Pneumology, Hubertus Wald-Tumor Zentrum (UCCH), University Hospital Eppendorf (UKE), Hamburg, Germany Melanie Braig, Department of Oncology, Haematology and Bone marrow transplantation with section Pneumology, Hubertus Wald-Tumor Zentrum (UCCH), University Hospital Eppendorf (UKE), Hamburg, Germany Valeska Wiehle, Klinik für Onkologie, Hämatologie und Stammzelltransplantation, Universitätsklinikum der RWTH, Aachen University, Aachen, Germany Susanne Ziegler, Klinik für Onkologie, Hämatologie und Stammzelltransplantation, Universitätsklinikum der RWTH, Aachen University, Aachen, Germany Marcus Schröder, Department of Chemistry, Organic Chemistry, Faculty of Sciences, Hamburg, Germany Chris Meier, Department of Chemistry, Organic Chemistry, Faculty of Sciences, Hamburg, Germany Adrian Kolodzik, Center for Bioinformatics, University of Hamburg, Hamburg, Germany Matthias Rarey, Center for Bioinformatics, University of Hamburg, Hamburg, Germany Jens Panse, Klinik für Onkologie, Hämatologie und Stammzelltransplantation, Universitätsklinikum der RWTH, Aachen University, Aachen, Germany Joachim Hauber, Heinrich Pette Institute - Leibniz Institute for Experimental Virology, Hamburg, Germany Stefan Balabanov, Department of Oncology, Haematology and Bone marrow transplantation with section Pneumology, Hubertus Wald-Tumor Zentrum (UCCH), University Hospital Eppendorf (UKE), Hamburg, Germany Tim H. Brümmendorf, Klinik für Onkologie, Hämatologie und Stammzelltransplantation, Universitätsklinikum der RWTH, Aachen University, Aachen, Germany Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Insulin like growth factor receptor (IGF-1R) targeting became one of the most investigated areas in anticancer drug development during the last decade. Strategies aiming to block IGF-1R activity include monoclonal antibodies, tyrosine kinase inhibitors and anti-ligands antibodies. Initial enthusiasm quickly encountered challenges. Unfortunately the validation of the efficacy of IGF-1R targeted agents in large clinical trials failed, however anecdotal single agent activity was seen in early studies. Consequently, questions regarding the selection of right target population and the appropriate trial design are arising. Despite the plethora of clinical trials conducted no predictive biomarker has been validated so far and resistance mechanisms to IGF-1R inhibitors remain unclear. The other issue to be addressed is how to best combine IGF-1R inhibitors with other therapeutic approaches. This review highlights the most relevant clinical data emphasizing the main tumor types where IGF-1R inhibition showed potential interest. We also tried to extract based on clinical and translational data some candidate biomarkers that could help better to select patient population who potentially could benefit most from this therapeutic approach. Content Type Journal Article Category REVIEW Pages 1-10 DOI 10.1007/s10637-012-9811-0 Authors Andrea Gombos, Medical Oncology Clinic, Institut Jules Bordet, 121 Boulevard de Waterloo, 1000 Brussels, Belgium Otto Metzger-Filho, Medical Oncology Clinic, Institut Jules Bordet, 121 Boulevard de Waterloo, 1000 Brussels, Belgium Lissandra Dal Lago, Medical Oncology Clinic, Institut Jules Bordet, 121 Boulevard de Waterloo, 1000 Brussels, Belgium Ahmad Awada-Hussein, Medical Oncology Clinic, Institut Jules Bordet, 121 Boulevard de Waterloo, 1000 Brussels, Belgium Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description: Erratum to: Assessment of the novel tubulin-binding agent EHT 6706 in combination with ionizing radiation or chemotherapy Content Type Journal Article Category Erratum Pages 1-3 DOI 10.1007/s10637-012-9799-5 Authors Céline Clémenson, INSERM U1030, Radiothérapie Moléculaire, Institut Gustave Roussy, Université Paris XI, Villejuif, France Cyrus Chargari, INSERM U1030, Radiothérapie Moléculaire, Institut Gustave Roussy, Université Paris XI, Villejuif, France Laurent Désiré, Exonhit SA, Paris, France Anne-Sophie Casagrande, Exonhit SA, Paris, France Jean Bourhis, INSERM U1030, Radiothérapie Moléculaire, Institut Gustave Roussy, Université Paris XI, Villejuif, France Eric Deutsch, INSERM U1030, Radiothérapie Moléculaire, Institut Gustave Roussy, Université Paris XI, Villejuif, France Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Background The combination of bevacizumab (B) and erlotinib (E) has shown promising clinical outcomes as the first-line treatment of advanced HCC patients. We aimed to evaluate the efficacy and safety of using combination of B + E in treating advanced HCC patients who had failed prior sorafenib treatment. Methods Eligible advanced HCC patients with documented radiological evidence of disease progression with sorafenib treatment were recruited. All patients received bevacizumab(B) at 10 mg/kg every 2 weeks with erlotinib(E) at 150 mg daily for a maximum of 6 cycles. Response assessments using both RECIST and modified RECIST criteria were performed after every 6 weeks. The primary endpoint was clinical benefit (CB) rate and a Simon two-stage design was employed. Results The trial was halted in the first stage according to the pre-set statistical criteria with 10 patients recruited. The median age was 47 years (range, 28–61) and all patients were in ECOG performance status 1. Eighty percent of patients were chronic hepatitis B carriers and all patients had Child A cirrhosis. Among these 10 patients, none of the enrolled patients achieved response or stable disease. The median time-to-progression was 1.81 months (95 % confidence interval [C.I.], 1.08–1.74 months) and overall survival was 4.37 months (95 % C.I., 1.08–11.66 months). Rash (70 %), diarrhea (50 %) and malaise (40 %) were the most commonly encountered toxicities. Conclusion The combination of B + E was well tolerated but had no activity in an unselected sorafenib-refractory advanced HCC population. Condensed abstract The combination of bevacizumab and erlotinib had no clinical activity in sorafenib-refractory HCC population. Content Type Journal Article Category PHASE II STUDIES Pages 1-7 DOI 10.1007/s10637-012-9808-8 Authors Thomas Yau, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Room 211B, 2/F New Clinical Building, 102 Pokfulam Road, Hong Kong, China Hilda Wong, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China Pierre Chan, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China T. J. Yao, Clinical Trials Centre, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China R. Pang, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Room 211B, 2/F New Clinical Building, 102 Pokfulam Road, Hong Kong, China T. T. Cheung, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Room 211B, 2/F New Clinical Building, 102 Pokfulam Road, Hong Kong, China S. T. Fan, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Room 211B, 2/F New Clinical Building, 102 Pokfulam Road, Hong Kong, China Ronnie T. Poon, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Room 211B, 2/F New Clinical Building, 102 Pokfulam Road, Hong Kong, China Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    A pharmacokinetic [PK]-driven screening process was implemented to select new agents for brain tumor chemotherapy from a series of low molecular weight anticancer agents [ON27x] that consisted of 141 compounds. The screening procedures involved a combination of in silico , in vitro and in vivo mouse studies that were cast into a pipeline of tier 1 and tier 2 failures that resulted in a final investigation of 2 analogues in brain tumor-bearing mice. Tier 1 failures included agents with a molecular weight of 〉 450 Da, a predicted log P (log P) of either 〈2 or 〉 3.5, and a cytotoxicity IC 50 value of 〉 2 uM. Next, 18 compounds underwent cassette dosing studies in normal mice that identified compounds with high systemic clearance, and low blood–brain barrier [BBB] penetration. These indices along with a derived parameter, referred to as the brain exposure index, comprised tier 2 failures that led to the administration of 2 compounds [ON27570, ON27740] as single agents [discrete dosing] to mice bearing intracerebral tumors. Comparison of ON27570’s resultant PK parameters to those obtained in the cassette dosing format suggested a drug-drug interaction most likely at the level of BBB transport, and prompted the use of the in vitro MDCK-MDR1 transport model to help assess the nature of the discrepancy. Overall, the approach was able to identify candidate compounds with suitable PK characteristics yet further revisions to the method, such as the use of in vitro metabolism and transport assays, may improve the PK-directed approach to identify efficacious agents for brain tumor chemotherapy. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-11 DOI 10.1007/s10637-012-9806-x Authors Hua Lv, Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA Fan Wang, Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA M. V. Ramana Reddy, Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA Qingyu Zhou, Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA Xiaoping Zhang, Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA E. Premkumar Reddy, Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA James M. Gallo, Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Pseudomyxoma peritonei is a disease characterised by the accumulation of mucinous ascites. Thus far, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to be effective at eradicating disease. Chemotherapy has been less effective, providing disease stabilization but not demonstrating significant treatment responses. Mucolytic is a potential class of drug that may be exploited in the chemical management of this disease. A variety of potential mucolytic agents are explored in this review providing evidence of basic biochemical evidence of its efficacy with potential translational application. Content Type Journal Article Category REVIEW Pages 1-7 DOI 10.1007/s10637-012-9797-7 Authors Krishna Pillai, Department of Surgery Cancer Research Laboratories, University of New South Wales, Sydney, Australia Javed Akhter, Department of Surgery Cancer Research Laboratories, University of New South Wales, Sydney, Australia Terence C. Chua, Department of Surgery Cancer Research Laboratories, University of New South Wales, Sydney, Australia David L. Morris, Department of Surgery Cancer Research Laboratories, University of New South Wales, Sydney, Australia Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Background Improvements in knowledge of molecular mechanisms in cancer are the basis for new studies combining chemotherapy with targeted drugs. Inhibition of the epidermal growth factor receptor (EGFR) by erlotinib or cetuximab has limited or no activity, respectively, in pancreatic cancer. The crosstalk between EGFR and mammalian target of rapamycin (mTOR) pathways is a potential mechanism of resistance; therefore we conducted a study to explore safety and efficacy of multiple pathway inhibition by cetuximab and everolimus in combination with capecitabine. Methods Safety and efficacy of fixed standard dose cetuximab in combination with various dose levels of everolimus (5–10 mg/day) and capecitabine (600–800 mg/m 2 bid, 2 weeks every 3 weeks) were investigated in a phase I/II study in patients with advanced pancreatic cancer. The primary endpoint was objective response. Results Sixteen patients were treated in the phase I part at two dose levels. Mucositis, rash and hand-foot syndrome were dose-limiting toxicities. Dose level 1 (everolimus 5 mg/day, capecitabine 600 mg/m 2 bid for 2 weeks every 3 weeks and cetuximab 250 mg/m 2 weekly) was considered the maximum tolerated dose (MTD). Of 31 patients in the phase II part, partial response was documented in two patients (6.5%) and five (16.1%) had stable disease. Median overall survival was 5.0 months (CI 3.1–6.8). Conclusion The schedule of capecitabine, everolimus and cetuximab resulted in considerable epidermal and mucosal toxicities and prevented escalation to optimal dose levels. Because of toxicity and low efficacy this treatment combination cannot be recommended for treatment in pancreatic cancer patients. Content Type Journal Article Category PHASE I STUDIES Pages 1-7 DOI 10.1007/s10637-012-9802-1 Authors Sil Kordes, Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Dick J. Richel, Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Heinz-Josef Klümpen, Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Mariëtte J. Weterman, Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Arnoldus J. W. M. Stevens, Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Johanna W. Wilmink, Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Purpose. Dasatinib is an oral tyrosine kinase inhibitor (TKI) of BCR-ABL and SRC family and ixabepilone is an epothilone B analog. Synergistic activity has been reported when combining dasatinib with chemotherapy. This study was conducted to determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTDs) for this combination. Patients and methods. Patients with metastatic solid tumors who progressed on standard therapy received dasatinib orally daily and ixabepilone IV every 3 weeks at escalating doses using 3 + 3 design. An expansion cohort was studied after reaching the MTD. Pharmacokinetic studies were performed. Results. Nineteen patients were enrolled. No DLTs were observed at dose level (DL) 1 (dasatinib 100 mg and ixabepilone 30 mg/m 2 ). At DL 2 (dasatinib 100 mg and ixabepilone 40 mg/m 2 ), one patient had multiple DLTs. At DL 3 (dasatinib 150 mg and ixabepilone 40 mg/m 2 ), the first patient developed grade 3 AE during cycle 2, the second patient had a DLT and a grade 3 AE during cycle 2. The accrual to DL 3 was halted without reaching the maximally administered dose (MAD) and MTDs were determined to be dasatinib 100 mg and ixabepilone 40 mg/m 2 (DL 2). One patient had a partial response and 12 patients stable disease as their best response. Fourteen patients came off study due to toxicities. Conclusion. The combination of dasatinib and ixabepilone showed modest clinical activity with doses 100 mg orally daily and 40 mg/m 2 IV every 3 weeks, respectively. Treatment related toxicities were seen frequently. Content Type Journal Article Category PHASE I STUDIES Pages 1-7 DOI 10.1007/s10637-012-9805-y Authors P. Herbolsheimer, Washington Cancer Institute (WCI)/ Medstar Washington Hospital Center (WHC), 110 Irving Street, NW, Washington, DC 20010, USA R. Kapoor, Washington Cancer Institute (WCI)/ Medstar Washington Hospital Center (WHC), 110 Irving Street, NW, Washington, DC 20010, USA K. L. Smith, Washington Cancer Institute (WCI)/ Medstar Washington Hospital Center (WHC), 110 Irving Street, NW, Washington, DC 20010, USA D. Perry, Washington Cancer Institute (WCI)/ Medstar Washington Hospital Center (WHC), 110 Irving Street, NW, Washington, DC 20010, USA N. Verma, Washington Cancer Institute (WCI)/ Medstar Washington Hospital Center (WHC), 110 Irving Street, NW, Washington, DC 20010, USA I. Veytsman, Washington Cancer Institute (WCI)/ Medstar Washington Hospital Center (WHC), 110 Irving Street, NW, Washington, DC 20010, USA J. Jelinek, Washington Cancer Institute (WCI)/ Medstar Washington Hospital Center (WHC), 110 Irving Street, NW, Washington, DC 20010, USA S. M. Swain, Washington Cancer Institute (WCI)/ Medstar Washington Hospital Center (WHC), 110 Irving Street, NW, Washington, DC 20010, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description: Background   Saracatinib (AZD0530) is a selective, oral Src inhibitor that has demonstrated antitumour activity in preclinical studies. Methods This open-label, dose-escalation, phase I study evaluated the safety and tolerability of saracatinib in Japanese patients with advanced solid tumours (clinicaltrials.gov NCT00704366). Patients received continuous once-daily oral dosing with saracatinib starting 7 days after a single dose in ascending dose cohorts until dose-limiting toxicity (DLT) or disease progression. Pharmacokinetics and efficacy were also evaluated. Results A total of 12 patients received saracatinib at doses of 50 ( n  = 3), 125 ( n  = 6), and 175 mg ( n  = 3). Median durations of exposure were 65, 44, and 16 days in the 50, 125, and 175 mg cohorts, respectively. The most common adverse events were diarrhoea (67 %), nausea (67 %), decreased appetite (58 %), lymphopenia (50 %) and pyrexia (50 %). The most common grade ≥3 adverse events were leukopenia, lymphopenia, neutropenia, and haemoglobin decreased (all 17 %). DLTs occurred in two patients, both in the 175 mg cohort: grade 3 aspartate aminotransferase increased with grade 3 gamma-glutamyltransferase increased ( n  = 1); and grade 3 hypoxia ( n  = 1). Following a single dose, saracatinib median t max across the doses was 2–4 h, and thereafter plasma concentrations declined in a biphasic manner, with mean terminal half-life of approximately 45 h. Geometric mean saracatinib exposures were 0.8–2.1 times greater than those reported in Caucasian patients. The best response was stable disease (50 mg, n  = 2; 125 mg, n  = 1). Conclusions Saracatinib was tolerated in Japanese patients with advanced solid tumours at doses up to 125 mg. Content Type Journal Article Category PHASE I STUDIES Pages 1-7 DOI 10.1007/s10637-012-9809-7 Authors Yasuhito Fujisaka, Osaka Medical College, Osaka, Japan Yusuke Onozawa, Shizuoka Cancer Center, Shizuoka, Japan Takayasu Kurata, Osaka Medical College, Osaka, Japan Hirofumi Yasui, Shizuoka Cancer Center, Shizuoka, Japan Isao Goto, Osaka Medical College, Osaka, Japan Kentaro Yamazaki, Shizuoka Cancer Center, Shizuoka, Japan Nozomu Machida, Shizuoka Cancer Center, Shizuoka, Japan Junichiro Watanabe, Shizuoka Cancer Center, Shizuoka, Japan Hitoshi Shimada, AstraZeneca, Osaka, Japan Xiaojin Shi, AstraZeneca, Osaka, Japan Narikazu Boku, Shizuoka Cancer Center, Shizuoka, Japan Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Persistent infections with certain high-risk human papillomavirus (HPV) types such as 16 and 18 can result in the development of cervical cancer. Neither of the two prophylactic vaccines against HPV16 and 18 that are in current use have any therapeutic efficacy for prevalent HPV infections. Ablative therapy is widely used for the treatment of HPV cervical dysplasia however disease recurrence is a widely recognized problem. Thus there is a continuing need for therapeutic approaches for the treatment of HPV infections. The HPV16 E6 viral oncoprotein represses surface expression of the cellular adhesion molecule, E-cadherin. Reduced E-cadherin expression on HPV-infected keratinocytes is associated with lowered numbers of antigen-presenting Langerhans cells in the infected epidermis, potentially reducing immune surveillance for HPV. Four chemicals reported to up-regulate E-cadherin were screened for their ability to counteract E6 repression of surface E-cadherin. 5-Aza-2’-deoxycytidine (AzaDC), a DNA methyltransferase inhibitor, and Indole-3-carbinol (I3C), reported to increase E-cadherin through a p21 Waf1/Cip1 -dependent mechanism, had low cytotoxicity and increased or restored E-cadherin expression and adhesive function in HPV16 E6 expressing HCT116 cells. Doxorubicin, also known to induce p21 Waf1/Cip1 , increased E-cadherin in E6 expressing cells but had some associated cytotoxicity. Tamoxifen, which can restore adhesive function of surface E-cadherin, was ineffective in counteracting E6 repression of E-cadherin. AzaDC and I3C both show potential to restore antigen-presenting cells to HPV infected skin by antagonizing E6 repression of E-cadherin, thereby counteracting an important immune evasion mechanism of HPV16 and reinstating immune function at the infected site. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-16 DOI 10.1007/s10637-012-9803-0 Authors Zarina J. D’Costa, Department of Microbiology and Immunology, University of Otago, P.O. Box 56, Dunedin, 9054 New Zealand Cheng-Mee Leong, Department of Microbiology and Immunology, University of Otago, P.O. Box 56, Dunedin, 9054 New Zealand Justin Shields, Department of Microbiology and Immunology, University of Otago, P.O. Box 56, Dunedin, 9054 New Zealand Charles Matthews, Department of Microbiology and Immunology, University of Otago, P.O. Box 56, Dunedin, 9054 New Zealand Merilyn H. Hibma, Department of Microbiology and Immunology, University of Otago, P.O. Box 56, Dunedin, 9054 New Zealand Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Background Ixabepilone, which stabilizes microtubules, has low susceptibility to drug resistance mediated by P-glycoprotein or βIII-tubulin. Materials and Methods This study was designed to determine the maximum tolerated dose (MTD) of oral ixabepilone when administered every 6 h for three doses, every 3 weeks, to patients with refractory advanced cancers. Eighteen patients were treated with escalating doses of ixabepilone: three at cohort 1 (30 mg/dose; 90 mg on Day 1), nine at cohort 2 (40 mg/dose; 120 mg on Day 1), and six at cohort 3 (50 mg/dose; 150 mg on Day 1). Serial plasma samples were collected during cycle 1 for pharmacokinetic (PK) measurements. Results Of the 18 treated patients, eight were male and ten were female. The median age was 59 years, and most had an excellent performance status (KPS 90–100; 61%). There were two dose limiting toxicities (DLT): Grade 4 febrile neutropenia at the 120 mg dose and Grade 4 neutropenic sepsis at the 150 mg dose. Because of the severity and duration of neutropenic sepsis at level 3, level 2 (120 mg) was defined as the MTD and this cohort was expanded to nine patients. High inter-individual variability in plasma drug concentrations was observed during the study, with particularly high levels in two patients with DLT. Conclusions On the basis of this safety profile, the MTD of oral ixabepilone was defined as 120 mg given as three 40 mg doses each separated by 6 h on Day 1 of a 3-week cycle. However, the PK variability observed makes further development of this oral formulation unlikely. Content Type Journal Article Category PHASE I STUDIES Pages 1-7 DOI 10.1007/s10637-012-9800-3 Authors Pamela L. Kunz, Stanford University School of Medicine, Stanford, CA, USA Aiwu R. He, Lombardi Comprehensive Cancer Center - Georgetown University, Washington, DC, USA A. Dimitrios Colevas, Stanford University School of Medicine, Stanford, CA, USA Michael J. Pishvaian, Lombardi Comprehensive Cancer Center - Georgetown University, Washington, DC, USA Jimmy J. Hwang, Lombardi Comprehensive Cancer Center - Georgetown University, Washington, DC, USA Pamela L. Clemens, Bristol-Myers Squibb, Princeton, NJ, USA Marianne Messina, Bristol-Myers Squibb, Wallingford, CT, USA Remigiusz Kaleta, Bristol-Myers Squibb, Wallingford, CT, USA Fernanda Abrahao, Bristol-Myers Squibb, Wallingford, CT, USA Branimir I. Sikic, Stanford University School of Medicine, Stanford, CA, USA John L. Marshall, Lombardi Comprehensive Cancer Center - Georgetown University, Washington, DC, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Proteasome inhibitors are emerging as a new class of anticancer agents. In this work, we examined the mechanisms underlying cytotoxicity, selectivity and adjuvant potential of the proteasome inhibitor MG132 in a panel of glioblastoma (GBM) cells (U138MG, C6, U87 and U373) and in normal astrocytes. MG132 markedly inhibited GBM cells growth irrespective of the p53 or PTEN mutational status of the cells whereas astrocytic viability was not affected, suggesting a selective toxicity of MG132 to cancerous glial cells. Mechanistically, MG132 arrested cells in G2/M phase of the cell cycle and increased p21 WAF1 protein immunocontent. Following cell arrest, cells become apoptotic as shown by annexin-V binding, caspase-3 activation, chromatin condensation and formation of sub-G1 apoptotic cells. MG132 promoted mitochondrial depolarization and decreased the mitochondrial antiapoptotic protein bcl-xL; it also induced activation of JNK and p38, and inhibition of NFkappaB and PI3K/Akt survival pathways. Pre-treatment of GBMs with the mitochondrial permeability transition pore inhibitor, bongkrekic acid, or pharmacological inhibitors of JNK1/2 and p38, SP600125 and SB203580, attenuated MG132-induced cell death. Besides its apoptotic effect alone, MG132 also enhanced the antiglioma effect of the chemotherapeutics cisplatin, taxol and doxorubicin in C6 and U138MG cells, indicating an adjuvant/chemosensitizer potential. In summary, MG132 exerted profound and selective toxicity in GBMs, being a potential agent for further testing in animal models of the disease. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-11 DOI 10.1007/s10637-012-9804-z Authors Alfeu Zanotto-Filho, Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brasil Elizandra Braganhol, Laboratório de Enzimologia, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brasil Ana Maria Oliveira Battastini, Laboratório de Enzimologia, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brasil José Cláudio Fonseca Moreira, Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brasil Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Red and brown algae have been shown to produce a variety of compounds with chemotherapeutic potential. A recent report described the isolation of a range of novel polyhalogenated monoterpene compounds from the red algae Plocamium corallorhiza and Plocamium cornutum collected off the coast of South Africa, together with the previously described tetraprenylquinone, sargaquinoic acid (SQA), from the brown algae Sargassum heterophyllum . In our study, the algal compounds were screened for anti-proliferative activity against metastatic MDA-MB-231 breast cancer cells revealing that a number of compounds displayed anti-cancer activity with IC 50 values in the micromolar range. A subset of the compounds was tested for differential toxicity in the MCF-7/MCF12A system and five of these, including sargaquinoic acid, were found to be at least three times more toxic to the breast cancer than the non-malignant cell line. SQA was further analysed in terms of its mechanism of cytotoxicity in MDA-MB-231 cells. The ability to initiate apoptosis was distinguished from the induction of an inflammatory necrotic response via flow cytometry with propidium iodide and Hoescht staining, confocal microscopy with Annexin V and propidium iodide staining as well as the PARP cleavage assay. We report that SQA induced apoptosis while a polyhalogenated monoterpene RU015 induced necrosis in metastatic breast cancer cells in vitro. Furthermore, we demonstrated that apoptosis induction by SQA occurs via caspase-3, -6, -8, -9 and -13 and was associated with down-regulation of Bcl-2. In addition, cell cycle analyses revealed that the compound causes G 1 arrest in MDA-MB-231 cells. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-14 DOI 10.1007/s10637-011-9788-0 Authors Jo-Anne de la Mare, The Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, P. O. Box 94, Grahamstown, 6140 South Africa Jessica C. Lawson, The Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, P. O. Box 94, Grahamstown, 6140 South Africa Maynard T. Chiwakata, Division of Pharmaceutical Chemistry, Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa Denzil R. Beukes, Division of Pharmaceutical Chemistry, Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa Adrienne L. Edkins, The Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, P. O. Box 94, Grahamstown, 6140 South Africa Gregory L. Blatch, The Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, P. O. Box 94, Grahamstown, 6140 South Africa Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Imatinib mesylate has proven activity in treating locally advanced or metastatic gastrointestinal stromal tumors (GIST). Drug interactions are particularly concerning as imatinib is extensively metabolized by the cytochrome P450 enzyme system. We describe the clinical course of a 72 year-old male with a cadaveric renal transplant requiring cyclosporine that presented with a metastatic GIST and was started on imatinib at the standard dose of 400 mg daily. Imatinib initiation resulted in a decline in renal function with the serum creatinine increasing from 123 μmol/L to 196 μmol/L and an elevation in whole blood cyclosporine concentrations from 79 μg/L to 139 μg/L. No other imatinib toxicities were reported. With discontinuation of imatinib, the serum creatinine returned to baseline as did the whole blood cyclosporine levels. Ultimately, decreasing both the cyclosporine and imatinib dosing was associated with stabilized renal function (serum creatinine 150–186 μmol/L) and cyclosporine concentrations (53–97 μg/L). A prolonged partial response to therapy for 19 months was maintained despite low imatinib trough concentrations measured on two separate occasions (127.1 ng/ml and 139 ng/ml). In our patient, imatinib initiation resulted in renal toxicity most likely due to its interaction with cyclosporine resulting in elevation of the whole blood cyclosporine concentration. Content Type Journal Article Category SHORT REPORT Pages 1-3 DOI 10.1007/s10637-011-9769-3 Authors Karen E. Mulder, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada Merrill J. Egorin, Departments of Medicine and Pharmacology and Cancer Center, Pittsburgh, Pennsylvania, USA Michael B. Sawyer, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Currently, no prospective data exists to support a “stop-and-go” modified FOLFOX6 regimen with bevacizumab in metastatic colorectal cancer (mCRC) patients. This study aimed to evaluate the efficacy and safety of this regimen in first-line mCRC patients. Eligible patients (age ≥20 years) had previously untreated mCRC; Eastern Cooperative Oncology Group performance status of 0–2; and adequate hematologic, hepatic, and renal function. The modified FOLFOX6 regimen and bevacizumab (5 mg/kg) was administered intravenously every 2 weeks. After 8 cycles, patients received maintenance therapy with simplified LV5FU2 and bevacizumab until completion of 8 cycles or disease progression. After maintenance therapy, patients received another 8 cycles of modified FOLFOX6 with bevacizumab until completion of 8 cycles or disease progression. We recruited 50 patients between August 2007 and January 2009. The overall response rate was 48% (80% confidence interval [CI]; 38.2–58) with outcomes as follows: complete response, n  = 1; partial response, n  = 23; stable disease, n  = 21; progression, n  = 1; and not evaluated, n  = 4. Median time to treatment failure was 7.7 months (80% CI: 6.2–8.0), and median progression-free survival was 12.8 months (80% CI: 10.8–14). Grade 3/4 toxicities included neutropenia (40%), nausea (4%), diarrhea (14%), thrombosis (4%), and hypertension (4%) et al. Grade 1, 2, or 3 peripheral neuropathy was reported in 38%, 40%, and 10% of patients, respectively. The stop-and-go modified FOLFOX6 and bevacizumab regimen is effective and well tolerated as first-line chemotherapy for mCRC patients. Content Type Journal Article Category PHASE II STUDIES Pages 1-6 DOI 10.1007/s10637-011-9779-1 Authors Natsuko T. Okita, Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045 Japan Taito Esaki, Gasrointestinal and Medical Oncology Division, National Kyushu Cancer Center, Fukuoka, Japan Eishi Baba, Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan Daisuke Sakai, Department of Clinical Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan Shinya Tokunaga, Department of Clinical Oncology, Osaka City General Hospital, Osaka, Japan Hiroya Takiuchi, Cancer Chemotherapy Center, Osaka Medical College Hospital, Osaka, Japan Nobuyuki Mizunuma, Department of Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan Kengo Nagashima, Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan Ken Kato, Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045 Japan Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Breast cancer is commonly treated with anti-estrogens or aromatase inhibitors, but resistant disease eventually develops and new therapies for such resistance are of great interest. We have previously isolated several tamoxifen-resistant variant sub-lines of the MCF-7 breast cancer cell line and provided evidence that they arose from expansion of pre-existing minor populations. We have searched for therapeutic agents that exhibit selective growth inhibition of the resistant lines and here investigate 2,6-bis(pyridin-3-ylmethylene)-cyclohexanone (RL90) and 2,6-bis(pyridin-4-ylmethylene)-cyclohexanone (RL91). We found that two of the tamoxifen-resistant sub-lines (TamR3 and TamC3) unexpectedly showed increased sensitivity to RL90 and RL91. We utilized growth inhibition assays, flow cytometry and immunoblotting to establish a mechanistic basis for their action. Treated sensitive cells showed S-phase selective DNA damage, as detected by histone H2AX phosphorylation. Cellular responses were similar to those induced by the topoisomerase I poison camptothecin. Although IC 50 values of camptothecin, RL90, RL91 were correlated, studies with purified mammalian topoisomerase I suggested that RL90 and RL91 differed from camptothecin by acting as catalytic topoisomerase I inhibitors. These drugs provide a platform for the further development of DNA damaging drugs that have selective effects on tamoxifen resistant breast cancer cells. The results also raise the question of whether clinical topoisomerase I poisons such as irinotecan and topotecan might be active in the treatment of some types of tamoxifen-resistant cancer. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-10 DOI 10.1007/s10637-011-9768-4 Authors Euphemia Leung, Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand Gordon W. Rewcastle, Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand Wayne R. Joseph, Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand Rhonda J. Rosengren, Department of Pharmacology & Toxicology, University of Otago, Dunedin, New Zealand Lesley Larsen, New Zealand Institute for Plant and Food Research Ltd, Dunedin, New Zealand Bruce C. Baguley, Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Sorafenib is an orally administered multikinase inhibitor that exhibits antiangiogenic and antitumor activity. Few investigators have been able to correlate cumulative sorafenib dose or total exposure to pharmacodynamic effects. This discrepancy may be in part due to poorly understood protein binding characteristics. Since unbound drug concentrations are believed to be more relevant to pharmacological and toxicological responses than total drug, an equilibrium dialysis method using 96-well microdialysis plates was optimized and validated for determining the fraction unbound (F u ) sorafenib in human plasma and in isolated protein solutions. Unbound sorafenib concentrations were determined in cancer patients receiving the drug orally at a dose of 400 mg and 600 mg twice daily. Sorafenib was extensively bound with mean F u value of 0.3% in both non-cancer and cancer patient’s plasma. The binding in plasma was concentration independent, indicating a low-affinity, possibly nonspecific and nonsaturable process. In isolated protein solutions, 99.8% and 79.3% of sorafenib was bound to human serum albumin (HSA) (4 g/dL) and α 1 -acid glycoprotein (AAG) (0.1 g/dL) with binding constants of 1.24 × 10 6  M −1 and 1.40 × 10 5  M −1 , respectively. In cancer patients receiving sorafenib, unbound sorafenib was not correlated with patient characteristics or laboratory values. In conclusion, sorafenib is highly protein bound in human plasma with a higher affinity towards albumin and limited free drug may be partly responsible for its borderline clinical activity. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-7 DOI 10.1007/s10637-011-9767-5 Authors Maria Cristina Villarroel, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Bldg, Room 1M52, 1650 Orleans Street, Baltimore, MD 21231-1000, USA Keith W. Pratz, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Bldg, Room 1M52, 1650 Orleans Street, Baltimore, MD 21231-1000, USA Linping Xu, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Bldg, Room 1M52, 1650 Orleans Street, Baltimore, MD 21231-1000, USA John J. Wright, Investigational Drug Branch/CTEP/NCI, Rockville, MD, USA B. Douglas Smith, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Bldg, Room 1M52, 1650 Orleans Street, Baltimore, MD 21231-1000, USA Michelle A. Rudek, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Bldg, Room 1M52, 1650 Orleans Street, Baltimore, MD 21231-1000, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Purpose Combining proteasome and histone deacetylase (HDAC) inhibition has been seen to provide synergistic anti-tumor activity, with complementary effects on a number of signaling pathways. The novel bi-cyclic structure of marizomib with its unique proteasome inhibition, toxicology and efficacy profiles, suggested utility in combining it with an HDAC inhibitor such as vorinostat. Thus, in this study in vitro studies assessed the potential utility of combining marizomib and vorinostat, followed by a clinical trial with the objectives of assessing the recommended phase 2 dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD), safety and preliminary anti-tumor activity of the combination in patients. Experimental Design Combinations of marizomib and vorinostat were assessed in vitro . Subsequently, in a Phase 1 clinical trial patients with melanoma, pancreatic carcinoma or Non-small Cell Lung Cancer (NSCLC) were given escalating doses of weekly marizomib in combination with vorinostat 300 mg daily for 16 days in 28 day cycles. In addition to standard safety studies, proteasome inhibition and pharmacokinetics were assayed. Results Marked synergy of marizomib and vorinostat was seen in tumor cell lines derived from patients with NSCLC, melanoma and pancreatic carcinoma. In the clinical trial, 22 patients were enrolled. Increased toxicity was not seen with the combination. Co-administration did not appear to affect the PK or PD of either drug in comparison to historical data. Although no responses were demonstrated using RECIST criteria, 61% of evaluable patients demonstrated stable disease with 39% having decreases in tumor measurements. Conclusions Treatment of multiple tumor cell lines with marizomib and vorinostat resulted in a highly synergistic antitumor activity. The combination of full dose marizomib with vorinostat is tolerable in patients with safety findings consistent with either drug alone. Content Type Journal Article Category PHASE I STUDIES Pages 1-15 DOI 10.1007/s10637-011-9766-6 Authors Michael Millward, Sir Charles Gairdner Hospital, University of Western Australia, Perth, Australia Timothy Price, The Queen Elizabeth Hospital, Adelaide, Australia Amanda Townsend, The Queen Elizabeth Hospital, Adelaide, Australia Christopher Sweeney, Royal Adelaide Hospital, Adelaide, Australia Andrew Spencer, The Alfred Hospital, Melbourne, Australia Shawgi Sukumaran, The Queen Elizabeth Hospital, Adelaide, Australia Angie Longenecker, Nereus Pharmaceuticals, Inc, 10480 Wateridge Circle, San Diego, CA 92121, USA Lonnie Lee, Nereus Pharmaceuticals, Inc, 10480 Wateridge Circle, San Diego, CA 92121, USA Ana Lay, Nereus Pharmaceuticals, Inc, 10480 Wateridge Circle, San Diego, CA 92121, USA Girish Sharma, Department of Medical University of South Carolina, Charleston, SC, USA Robert M. Gemmill, Department of Medical University of South Carolina, Charleston, SC, USA Harry A. Drabkin, Department of Medical University of South Carolina, Charleston, SC, USA G. Kenneth Lloyd, Nereus Pharmaceuticals, Inc, 10480 Wateridge Circle, San Diego, CA 92121, USA Saskia T. C. Neuteboom, Nereus Pharmaceuticals, Inc, 10480 Wateridge Circle, San Diego, CA 92121, USA David J. McConkey, MD Anderson Cancer Center, Houston, TX, USA Michael A. Palladino, Nereus Pharmaceuticals, Inc, 10480 Wateridge Circle, San Diego, CA 92121, USA Matthew A. Spear, Nereus Pharmaceuticals, Inc, 10480 Wateridge Circle, San Diego, CA 92121, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Glioblastoma represent the most frequent primary tumors of the central nervous system and remain among the most aggressive human cancers as available therapeutic approaches still fail to contain their invasiveness. Many studies have reported elevated expression of the Focal Adhesion Kinase (FAK) protein in glioblastoma, associated with an increase in the rates of both migration and invasion. This designates FAK as a promising target to limit invasiveness in glioblastoma. Thymoquinone (TQ), the main phytoactive compound of Nigella sativa has shown remarkable anti-neoplasic activities on a variety of cancer cells. Here, we studied the anti-invasive and anti-migratory effects of TQ on human glioblastoma cells. The results obtained indicated that TQ treatment reduced migration, adhesion and invasion of both U-87 and CCF-STTG1 cells. This was accompanied by a drastic down-regulation of FAK, associated with a reduction of ERK phosphorylation as well as MMP-2 and MMP-9 secretion. This study provides new data on FAK regulation by a natural product (TQ) which could be of a great value for the development of novel therapies in glioblastoma. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-11 DOI 10.1007/s10637-011-9777-3 Authors Kaouther Kolli-Bouhafs, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, CNRS UMR 7213, 74 route du Rhin, B.P. 60024, 67401 Illkirch, France Abdelaziz Boukhari, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, CNRS UMR 7213, 74 route du Rhin, B.P. 60024, 67401 Illkirch, France Abdurazzag Abusnina, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, CNRS UMR 7213, 74 route du Rhin, B.P. 60024, 67401 Illkirch, France Emilie Velot, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, CNRS UMR 7213, 74 route du Rhin, B.P. 60024, 67401 Illkirch, France Jean-Pierre Gies, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, CNRS UMR 7213, 74 route du Rhin, B.P. 60024, 67401 Illkirch, France Claire Lugnier, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, CNRS UMR 7213, 74 route du Rhin, B.P. 60024, 67401 Illkirch, France Philippe Rondé, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, CNRS UMR 7213, 74 route du Rhin, B.P. 60024, 67401 Illkirch, France Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    The poly-(ADP-ribose) polymerase (PARP) inhibitor, MK-4827, is a novel potent, orally bioavailable PARP-1 and PARP-2 inhibitor currently in phase I clinical trials for cancer treatment. No preclinical data currently exist on the combination of MK-4827 with radiotherapy. The current study examined combined treatment efficacy of MK-4827 and fractionated radiotherapy using a variety of human tumor xenografts of differing p53 status: Calu-6 (p53 null), A549 (p53 wild-type [wt]) and H-460 (p53 wt) lung cancers and triple negative MDA-MB-231 human breast carcinoma. To mimic clinical application of radiotherapy, fractionated radiation (2 Gy per fraction) schedules given once or twice daily for 1 to 2 weeks combined with MK-4827, 50 mg/kg once daily or 25 mg/kg twice daily, were used. MK-4827 was found to be highly and similarly effective in both radiation schedules but maximum radiation enhancement was observed when MK-4827 was given at a dose of 50 mg/kg once daily ( EF  = 2.2). MK-4827 radiosensitized all four tumors studied regardless of their p53 status. MK-4827 reduced PAR levels in tumors by 1 h after administration which persisted for up to 24 h. This long period of PARP inhibition potentially adds to the flexibility of design of future clinical trials. Thus, MK-4827 shows high potential to improve the efficacy of radiotherapy. Content Type Journal Article Category PRECLINICAL STUDIES Pages 1-8 DOI 10.1007/s10637-011-9770-x Authors Li Wang, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Unit 066, 1515 Holcombe Blvd, Houston, TX 77030, USA Kathy A. Mason, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Unit 066, 1515 Holcombe Blvd, Houston, TX 77030, USA K. Kian Ang, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Thomas Buchholz, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA David Valdecanas, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Unit 066, 1515 Holcombe Blvd, Houston, TX 77030, USA Anjili Mathur, Department of Oncology, Merck Research Labs, 33 Avenue Louis Pasteur, Boston, MA 02115, USA Carolyn Buser-Doepner, Department of Oncology, Merck Research Labs, 33 Avenue Louis Pasteur, Boston, MA 02115, USA Carlo Toniatti, Department of Oncology, Merck Research Labs, 33 Avenue Louis Pasteur, Boston, MA 02115, USA Luka Milas, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Unit 066, 1515 Holcombe Blvd, Houston, TX 77030, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description: Erratum to: Phase I trial of sorafenib in combination with interferon-alpha in Japanese patients with unresectable or metastatic renal cell carcinoma Content Type Journal Article Category Erratum Pages 1-2 DOI 10.1007/s10637-011-9771-9 Authors Masashi Niwakawa, Division of Urology, Shizuoka Cancer Center Hospital, 1007 Shimonagakubo, Nagaizumi, Shizuoka, 411-8777 Japan Katsuyoshi Hashine, Department of Urology, National Hospital Organization, Shikoku Cancer Center, Ehime, Japan Raizo Yamaguchi, Division of Urology, Shizuoka Cancer Center Hospital, 1007 Shimonagakubo, Nagaizumi, Shizuoka, 411-8777 Japan Hirofumi Fujii, Division of Clinical Oncology, Jichi Medical University, Tochigi, Japan Yasuo Hamamoto, Department of Medical Oncology, Tochigi Cancer Center Hospital, Tochigi, Japan Koichi Fukino, Bayer Yakuhin, Ltd., Osaka, Japan Takahiko Tanigawa, Bayer Yakuhin, Ltd., Osaka, Japan Yoshiteru Sumiyoshi, Department of Urology, National Hospital Organization, Shikoku Cancer Center, Ehime, Japan Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Purpose This phase I trial assessed the safety, maximally tolerated dose (MTD) and pharmacokinetics of TRKA/CDK inhibitor PHA-848125AC in adult patients with advanced/metastatic solid tumors. Patients and methods Patients with relapsed or refractory solid tumors, for which no standard therapy existed, were eligible. PHA-848125AC was administered orally in two schedules: daily for 7 consecutive days in 2-week cycles (i.e. 7 days on/7 days off q2wks; S1) or daily for 4 consecutive days a week for 3 weeks in 4-week cycles (i.e. 4 days on/3 days off x 3wks q4wks; S2). Results Thirty-seven patients were treated in this study, 22 in S1 and 15 in S2. The recommended phase II dose (RP2D) was 150 mg/day for either schedule. The dose-limiting toxicities (DLTs) in S1 included ataxia (Grade 2–4) and tremors (Grade 2–3). In S2, DLTs included tremors (Grade 2–3), elevated lipase (Grade 3), increased creatinine (Grade 2), and nausea and vomiting (Grade 3). These events were all reversible. In S2, out of 14 patients evaluable for efficacy, 2 patients with thymic carcinoma, showed partial response and stable disease was observed in 3 patients. Stable disease was observed in 6 out 14 patients evaluable for efficacy on S1. Drug pharmacokinetics demonstrated a half-life of approximately 33 h, and dose-proportionality with accumulation by a factor of 3 after repeated administrations. Conclusion The RP2D of PHA-848125AC was 150 mg/day on both schedules. Based on the responses noted in thymic carcinoma, a phase II study for patients with that disease is currently enrolling. Content Type Journal Article Category PHASE I STUDIES Pages 1-10 DOI 10.1007/s10637-011-9774-6 Authors Glen J. Weiss, Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC), 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Manuel Hidalgo, Johns Hopkins, Baltimore, MD, USA Mitesh J. Borad, Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC), 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Daniel Laheru, Johns Hopkins, Baltimore, MD, USA Raoul Tibes, Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC), 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Ramesh K. Ramanathan, Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC), 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Lisa Blaydorn, Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC), 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Gayle Jameson, Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC), 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Antonio Jimeno, Johns Hopkins, Baltimore, MD, USA Jeffrey D. Isaacs, Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC), 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Angela Scaburri, Milano International Oncology (MIO), Nerviano Medical Sciences S.r.l., Nerviano, Milan, Italy Maria Adele Pacciarini, Milano International Oncology (MIO), Nerviano Medical Sciences S.r.l., Nerviano, Milan, Italy Francesco Fiorentini, Accelera S.r.l, Nerviano, Milan, Italy Marina Ciomei, Oncology, Nerviano Medical Sciences S.r.l., Nerviano, Milan, Italy Daniel D. Von Hoff, Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC), 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    Purpose This phase I trial was designed to determine the recommended phase II dose(s) of everolimus (RAD001) with temozolomide (TMZ) in patients with glioblastoma (GBM). Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and those not receiving EIAEDs (NEIAEDs) were studied separately. Patients and Methods Enrollment was restricted to patients with proven GBM, either newly diagnosed or at first progression. Temozolomide was administered at a starting dose of 150 mg/m 2 /day for 5 days every 28 days, and everolimus was administered continuously at a starting dose of 2.5 mg orally on a daily schedule starting on day 2 of cycle 1 in 28-day cycles. Results Thirteen patients receiving EIAEDs and 19 not receiving EIAEDs were enrolled and received 83 and 116 cycles respectively. Everolimus 10 mg daily plus TMZ 150 mg/m 2 /day for 5 days was declared the recommended phase II dose for the NEIAEDs cohort. In the EIAEDs group, doses were well tolerated without DLTs, and pharmacokinetic parameters indicated decreased everolimus exposure. Temozolomide pharmacokinetic parameters were unaffected by EIAEDs or everolimus. In the subset of 28 patients with measurable disease, 3 had partial responses (all NEIAEDs) and 16 had stable disease. Conclusion A dosage of 10 mg everolimus daily with TMZ 150 mg/m 2 /day for five consecutive days every 28 days in patients is the recommended dose for this regimen. Everolimus clearance is increased by EIAEDs, and patients receiving EIAEDs should be switched to NEIAEDs before starting this regimen. Content Type Journal Article Category PHASE I STUDIES Pages 1-8 DOI 10.1007/s10637-011-9775-5 Authors Warren P. Mason, University Health Network-Princess Margaret Hospital, 610 University Avenue, Suite 18-717, Toronto, ON M5G 2M9, Canada Mary MacNeil, QEII Health Sciences Centre, Halifax, Canada Petr Kavan, Department of Oncology, McGill University, Montréal, Canada Jacob Easaw, Tom Baker Cancer Centre, Calgary, Canada David Macdonald, London Regional Cancer Centre, London, Canada Brian Thiessen, BCCA–Vancouver Cancer Centre, Victoria, Canada Shweta Urva, Novartis Pharmaceuticals Corporation- Oncology Business Unit, Florham Park, USA Zarnie Lwin, University Health Network-Princess Margaret Hospital, 610 University Avenue, Suite 18-717, Toronto, ON M5G 2M9, Canada Lynn McIntosh, NCIC Clinical Trials Group, Kingston, Canada Elizabeth Eisenhauer, NCIC Clinical Trials Group, Kingston, Canada Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997

Description:    The kinetic principles of sorption of formaldehyde sorption on a polyfunctional weak-basic anion exchanger are considered. It is found that the limiting step of sorbate uptake is external diffusion. Parameters of formaldehyde sorption from aqueous solutions under dynamic conditions are determined. Content Type Journal Article Category Short Communications Pages 884-885 DOI 10.1134/S0036024412050354 Authors I. V. Voronyuk, Voronezh State University, Voronezh, Russia T. V. Eliseeva, Voronezh State University, Voronezh, Russia V. F. Selemenev, Voronezh State University, Voronezh, Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 5

Description:    The kinetics of tin oxidation was studied using Auger spectroscopy and characteristic electron energy loss spectroscopy. Studies were performed with continuous electron irradiation ( E p = 1800 eV) and without it depending on exposition in oxygen medium at a 10 −6 torr partial oxygen pressure and room temperature (maximum exposure in oxygen was 3000 Langmuir). Exposition to oxygen at 3000 L was shown to cause the formation of a continuous SnO 2 oxide layer, whereas electron irradiation with the same exposition stimulated the growth of a layer predominantly containing SnO. Content Type Journal Article Category Chemical Kinetics and Catalysis Pages 752-756 DOI 10.1134/S0036024412050032 Authors O. G. Ashkhotov, Kabardino-Balkar State University, ul. Chernyshevskogo 173, Nalchik, 360004 Russia I. B. Ashkhotova, Kabardino-Balkar State University, ul. Chernyshevskogo 173, Nalchik, 360004 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 5

Description:    A 16-constant additive scheme was derived for calculating the physicochemical properties of saturated monoalcohols CH 4 O-C 9 H 20 O and decomposing the triangular numbers of the Pascal triangle based on the similarity of subgraphs in the molecular graphs (MGs) of the homologous series of these alcohols. It was shown, using this scheme for calculation of properties of saturated monoalcohols as an example, that each coefficient of the scheme (in other words, the number of methods to impose a chain of a definite length i 1 , i 2 , … on a molecular graph) is the result of the decomposition of the triangular numbers of the Pascal triangle. A linear dependence was found within the adopted classification of structural elements. Sixteen parameters of the schemes were recorded as linear combinations of 17 parameters. The enthalpies of vaporization L 298 K 0 of the saturated monoalcohols CH 4 O-C 9 H 20 O, for which there were no experimental data, were calculated. It was shown that the parameters are not chosen randomly when using the given procedure for constructing an additive scheme by decomposing the triangular numbers of the Pascal triangle. Content Type Journal Article Category Chemical Thermodynamics and Thermochemistry Pages 736-740 DOI 10.1134/S0036024412050123 Authors V. V. Grebeshkov, Tver State University, Tver, Russia V. M. Smolyakov, Tver State University, Tver, Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 5

Description:    Calorimetric measurements were performed and the heat effects of sorption of ammonium ions from aqueous solutions by the M 45 K 20 natural sorbent and its acid- and alkali-activated forms were calculated. Content Type Journal Article Category Physical Chemistry of Surface Phenomena Pages 849-851 DOI 10.1134/S0036024412050214 Authors Ly Tkhi Ien, Voronezh State University, Universitetskaya pl. 1, Voronezh, 394893 Russia V. Yu. Khokhlov, Voronezh State University, Universitetskaya pl. 1, Voronezh, 394893 Russia L. P. Bondareva, Voronezh State Technological Academy, pr. Revolyutsii 19, Voronezh, 394017 Russia L. I. Bel’chinskaya, Voronezh Forestry Engineering Academy, Voronezh, Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 5

Description:    Peculiarities of the chromatographic behavior of adamantylamidrazones and adamantyltriazoles on octadecyl silica gel and hypercrosslinked polystyrenes in the conditions of reverse phase high performance chromatography are investigated. A comparative analysis of the effect of structures and physicochemical characteristics of sorbate molecules on the Gibbs free energy of sorption for the investigated sorbates is performed. Content Type Journal Article Category Physical Chemistry of Separation Processes: Chromatography Pages 852-859 DOI 10.1134/S0036024412050299 Authors S. V. Prokopov, Samara State University, Samara, 443011 Russia S. V. Kurbatova, Samara State University, Samara, 443011 Russia V. A. Davankov, Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow, 119991 Russia M. A. Il’in, Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow, 119991 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 5

Description:    The adsorption of methane on MN-200 and MN-270 polymer adsorbents, and on active carbon D4609, is investigated in the pressure range of 0.1–40 MPa at temperatures of 303, 323, 343, 373 K. Adsorption volumes are determined for these adsorption systems, and the isosteric heats of adsorption are calculated. Based on our investigations, we consider the possibility of storing methane in the adsorbed state in containers and the efficiency of the approach relative to gas storage in containers without adsorbents. Recommendations on selecting an adsorbent for methane storage are given, and one possible way of increasing the amount of stored gas is described. Content Type Journal Article Category Physical Chemistry of Surface Phenomena Pages 837-842 DOI 10.1134/S0036024412050287 Authors A. A. Pribylov, Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Moscow, 119991 Russia I. A. Kalinnikova, Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Moscow, 119991 Russia L. G. Shekhovtsova, Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Moscow, 119991 Russia V. A. Davankov, Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow, 119991 Russia M. P. Tsyurupa, Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow, 119991 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 5

Description:    Our study using the nonlocal density functional theory (NDFT) showed that active coals might have a bidisperse microporous structure. The binomial equation of the theory of volume filling of micropores (TVFM) approximates well the nitrogen adsorption isotherms at relative pressures from 1 × 10 −4 to 0.2. The dominant micropore sizes calculated in terms of the characteristic adsorption energy lie in the region of the maximum of the size distribution of micropores calculated by the NDFT method. The tentative micropore sizes can be determined from the modified second term of the TVFM equation. The Henry and BET equations describe very limited regions of the nitrogen adsorption isotherm on microporous active coals. Content Type Journal Article Category Physical Chemistry of Surface Phenomena Pages 843-848 DOI 10.1134/S0036024412050147 Authors R. I. Ibragimova, St. Petersburg State University of Technology and Design, St. Petersburg, Russia S. F. Grebennikov, St. Petersburg State University of Technology and Design, St. Petersburg, Russia V. V. Gur’yanov, OAO Neorganika, Elektrostal, Russia N. V. Vorob’ev-Desyatovskii, ZAO Polymetal Engineering, St. Petersburg, Russia S. A. Kubyshkin, St. Petersburg State University of Technology and Design, St. Petersburg, Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 5

Description:    In this research work, the effect of solvent on the size of paltinum nanoparticles synthesized by microemulsion method was investigated. Platinum nanoparticles have been prepared by the reduction of H 2 PtCl 6 with hydrazine in water-in-oil (w/o) microemulsions consisting of sodium bis(2-ethylhexyl) sulfo-succinate (AOT) and solvents n -hexane, cyclohexane and n -nonane. The size of the platinum nanoparticles was measured using transmission electron microscopy (TEM). It was verified that, for reduction of H 2 PtCl 6 by hydrazine in microemulsion with different organic solvents, the solvents are arranged by their influence on nanoparticle sizes as follows: n -nonane 〉 cyclohexane 〉 n -hexane. Content Type Journal Article Category Short Communications Pages 881-883 DOI 10.1134/S0036024412050020 Authors Alireza Salabat, Department of Chemistry, Arak University, Arak, 38156-8-8349 Iran Mina Rahmati Far, Department of Chemistry, Arak University, Arak, 38156-8-8349 Iran Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 5

Description:    The enthalpy of reaction of metallic calcium with perchloric acid was measured for the first time in a sealed swinging calorimeter equipped with an isothermal shell. Standard enthalpies of formation of calcium ion in an infinitely diluted aqueous solution (−542.8 ± 1.0 kJ/mol) and calcium chloride in crystal state (−794.9 ± 1.0 kJ/mol) were calculated according to the results obtained with the use of published data. Content Type Journal Article Category Short Communications Pages 886-888 DOI 10.1134/S0036024412050251 Authors A. S. Monaenkova, Department of Chemistry, Moscow State University, Moscow, 119991 Russia L. A. Tiflova, Department of Chemistry, Moscow State University, Moscow, 119991 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 5

Description:    Molecular masses of the complexes that form upon the reaction of (2- p Tolylindenyl) 2 ZrMe 2 with AlBu 3 i in toluene at room temperature were determined by means of electrospray mass spectrometry. It was determined that zirconium is arranged between two dimeric clusters with the monozirconium cation (L 2 ZrBu i + · HAlBu 3 i − ) 2 and dizirconium cation {[L 2 ZrBu i (μ-CH 3 )Bu i ZrL 2 ] + · HAlBu 3 i − } 2 in these complexes. Content Type Journal Article Category Short Communications Pages 875-877 DOI 10.1134/S003602441205010X Authors Z. M. Dzhabieva, Institute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka, Moscow oblast, 142432 Russia S. V. Topilin, Institute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka, Moscow oblast, 142432 Russia T. S. Dzhabiev, Institute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka, Moscow oblast, 142432 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 5

Description:    The thermodynamic equilibrium in the carbon dioxide conversion of methane is studied by Gibbs energy minimization. The curves that represent the dependences of the degree of coke formation, the content of methane and carbon dioxide in syngas, and the syngas module on the CO 2 /CH 4 mole ratio in the initial mixture and on temperature at various pressures, are plotted. The regions in which the CO 2 /CH 4 mole ratio is optimal for carbon dioxide conversion and no coke formation occurs, and which are characterized by a minimal content of methane and carbon dioxide in syngas, are revealed. Content Type Journal Article Category Chemical Thermodynamics and Thermochemistry Pages 741-746 DOI 10.1134/S0036024412050305 Authors O. N. Protasov, United Research and Development Centre, Moscow, 119333 Russia N. A. Mamonov, United Research and Development Centre, Moscow, 119333 Russia M. N. Mikhailov, United Research and Development Centre, Moscow, 119333 Russia L. M. Kustov, Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, 119991 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 5

Description:    The water-dimethyl sulfoxide (DMSO) system was studied by means of static light scattering in the concentration range of 0 to 60 mol % DMSO at 20 and 50°C. In the concentration range of 10 mol % DMSO, an abnormal maximum of scattered light was detected, the intensity of which decreases with an increase of temperature. The formation of this maximum is related to hydrophobic effects in the system under study and the existence of an unattainable critical point of delayering. Temperature inversion of light scattering intensity was detected at ∼14 mol % DMSO; at higher concentrations of DMSO, the intensity at 50°C is notably higher than at 20°C (due to the increase in the concentration’s degree of fluctuation upon an increase in temperature); at 60 mol % DMSO, intensities of scattered light at 20 and 50°C almost coincide. The apparent molar volumes of DMSO in solutions were calculated from the published data on density in the temperature range of 5 to 50°C. The minima of these values from 10 to 15 mol % DMSO (i.e., in the range of the abnormal maximum of scattered light) were obtained. The manifestation of hydrophobic effects in aqueous solutions of amphiphilic molecules is explained using the example of the DMSO-H 2 O system. Content Type Journal Article Category Short Communications Pages 892-894 DOI 10.1134/S0036024412050317 Authors M. N. Rodnikova, Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Moscow, 117901 Russia Yu. A. Zakharova, Department of Chemistry, Moscow State University, Moscow, 119991 Russia I. A. Solonina, Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Moscow, 117901 Russia D. A. Sirotkin, Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Moscow, 117901 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 5

Description:    A correlation is found between the proton spin-spin relaxation times in gold nanocomposites based on arabinogalactan in aqueous solutions and the maximum conducting layer thicknesses of films cast from solutions of composites. The obtained correlation is considered from the viewpoint of electrization’s effect on the mobility of macromolecules of the investigated polymer nanocomposites. The dependence of arabinogalactan mobility on the type of solvent (H 2 O or D 2 O) is established, and a conclusion is drawn as to the effect of the hydrogen bonds of arabinogalactan with solvent on polymer mobility in solutions. Content Type Journal Article Category Physical Chemistry of Nanoclusters and Nanomaterials Pages 812-815 DOI 10.1134/S0036024412050263 Authors M. N. Nikolaeva, Institute of Macromolecular Compounds, Russian Academy of Sciences, St. Petersburg, 199004 Russia G. P. Aleksandrova, Favorsky Institute of Chemistry, Irkutsk, 664033 Russia A. A. Martynenkov, Institute of Macromolecular Compounds, Russian Academy of Sciences, St. Petersburg, 199004 Russia Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 5

Description:    Heterogeneous photocatalytic removal of Rhodamine-B (RhB) dye from liquid phase was done using mixed-phase nanocrystalline TiO 2 for enhancement of charge separation and UV-visible-light-driven photocatalysis capabilities. The mixed-phase nanocrystalline TiO 2 was characterized using various analytical techniques including XRD, TEM, UV-vis DRS and PL to investigate its phase composition and structure, nanocrystalline size distribution, band gap energy, and photoluminescence properties. The photocatalytic discoloration efficiency of mixed-phase nanocrystalline titania was explored by monitoring the decomposition of RhB dye in an aqueous solution. The results showed that the as-prepared mixed-phase nanocrystalline TiO 2 was excellent for degradation of RhB molecule, and the combination of crystal phase of anatase and rutile has great effect on decomposition of RhB. The kinetic studies demonstrate that the photocatalytic oxidation reaction followed a pseudo-first-order expression due to the evidence of linear correlation between ln( c/c 0 ) vs. reaction time t . Moreover, the aqueous RhB dye decomposition over the as-prepared mixed-phase nanocrystalline TiO 2 catalyst is controlled by RhB pre-adsorption. Content Type Journal Article Category Physical Chemistry of Nanoclusters and Nanomaterials Pages 805-811 DOI 10.1134/S0036024412050081 Authors Dongfang Zhang, College of Science, Huazhong Agricultural University, Hongshan, 430070 P.R. China Journal Russian Journal of Physical Chemistry A, Focus on Chemistry Online ISSN 1531-863X Print ISSN 0036-0244 Journal Volume Volume 86 Journal Issue Volume 86, Number 5