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  • Articles  (27)
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  • 1995-1999  (27)
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  • Articles  (27)
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  • Springer  (27)
  • American Geophysical Union
  • Cell Press
  • Emerald
  • International Union of Crystallography
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  • 2000-2004
  • 1995-1999  (27)
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  • 1
    Electronic Resource
    Electronic Resource
    Apoptosis and p53 gene expression in male reproductive tissues of cadmium exposed rats (1999)
    Springer
    BioMetals 12 (1999), S. 131-139 
    Details
    ISSN: 1572-8773
    Keywords: cadmium ; apoptosis ; RT-PCR ; p53 gene expression ; testes ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Reverse transcription (RT) PCR technique was used to investigate the mechanism of apoptosis induced by Cd and the change of its related genes in testes and prostate of rats. Adult male rats were given a single (s.c.) injection of CdC l2 0, 2.5, 5.0, 10 μmol/kg. 48 h and 72 h after administration of Cd, animals were sacrificed. The results indicated that Cd can induce apoptosis in testes via p53-independent pathway. No apoptosis occurred in prostate in any of the Cd-exposed groups. There was a clearly negative relationship in testes between p53 gene expression and Cd exposure and this dose-response relationship was observed both at 48 h and 72 h. There was a very small increase of this gene expression in the dorsolateral lobe of the prostate in Cd exposed groups. The other apoptosis related gene, bcl-x, was not detectable in either control or Cd-exposed group in testes and dorsal prostate. Although the MT-I gene was expressed in testes or dorsal prostate both in control and exposed groups, no overexpression of MT-I gene was found after administration of Cd . The expression of MT-I in the ventral prostate was not detected in the control group, but a weak expression was found after Cd exposure. Since p53 is a tumo r suppressor gene which can inhibit tumorigenesis, the consequence of a Cd-induced decrease of p53 in testes may have a relation to the known risk of Cd tumorigenesis in this tissue.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009273711068
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  • 2
    Electronic Resource
    Electronic Resource
    Regulation of cardiomyocyte apoptosis in ischemic reperfused mouse heart by glutathione peroxidase (1999)
    Springer
    Molecular and cellular biochemistry 196 (1999), S. 13-21 
    Details
    ISSN: 1573-4919
    Keywords: apoptosis ; DNA fragmentation ; GSHPx-1 knockout mice ; GSHPx-1 transgenic mice ; ischemia/repurfusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Apoptosis, a genetically controlled programmed cell death, has been found to play a role in ischemic reperfusion injury in several animal species including rats and rabbits. To examine whether this is also true for other animals, an isolated perfused mouse heart was subjected to 30 min of ischemia followed by 2 h of reperfusion. Experiments were terminated before ischemia (baseline), after ischemia, and at 30, 60, 90 and 120 min of reperfusion. At the end of each experiment, hearts were processed for the evaluation of apoptosis and DNA laddering. The in situ end labeling (ISEL) technique was used to detect apoptotic cardiomyocyte nuclei while DNA laddering was evaluated by subjecting the DNA obtained from the cardiomyocytes to 1.8% agarose gel electrophoresis followed by photographing under UV illumination. The results of our study revealed that apoptotic cells appear only after 60 min of reperfusion as demonstrated by the intense fluorescence of the immunostained genomic DNA when observed under fluorescence microscopy. None of the ischemic hearts showed any evidence of apoptosis. These results were corroborated with the findings of DNA fragmentation showing increased ladders of DNA bands in the same reperfused hearts representing integer multiples of the internucleosomal DNA length (about 180 bp). Since our previous studies showed a role of glutathione peroxidase (GSHPx) in apoptotic cell death, we performed identical experiments using isolated hearts from GSHPx-l knockout mice and transgenic mice overexpressing GSHPx-l. GSHPx-l knockout mice showed evidence of apoptotic cell death even after 30 min of reperfusion. Significant number of apoptotic cells were found in the cardiomyocytes as compared to non-transgenic control animals. To the contrary, very few apoptotic cells were found in the hearts of the transgenic mice overexpressing GSHPx-l. Hearts of GSHPx-l knockout mice were more susceptible to ischemia/reperfusion injury while transgenic mice overexpressing GSHPx- 1 were less susceptible to ischemia reperfusion injury compared to non-transgenic control animals. The results of this study clearly demonstrate a role of GSHPx in ischemia/reperfusion-induced apoptosis in mouse heart.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006905910140
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  • 3
    Electronic Resource
    Electronic Resource
    Human DU145 prostate cancer cells overexpressing mitogen-activated protein kinase phosphatase-1 are resistant to Fas ligand-induced mitochondrial perturbations and cellular apoptosis (1999)
    Springer
    Molecular and cellular biochemistry 199 (1999), S. 169-178 
    Details
    ISSN: 1573-4919
    Keywords: MKP-1 ; Fas ligand ; Fas ; apoptosis ; prostate cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Recent studies have suggested that MAP kinase phosphatase 1 (MKP-1) is overexpressed in prostate cancer. To evaluate the role of MKP-1 in regulating cell death and tumor growth in prostate cancer, MKP-1 was conditionally overexpressed in the human prostate cancer cell line DU145. Overexpression of MKP-1 in DU145 cells blocked activation of stress-activated protein kinase (SAPK/JNK). MKP-1 overexpression in DU-145 cells was also found to inhibit Fas ligand (FasL)-induced apoptosis, as well as block the activation of caspases by Fas engagement. In addition, MKP-1 blocked the activation of apoptosis by transfected MEKK-1 and ASK-1, presumably through its inhibition of the SAPK/JNK family of enzymes. MKP-1 blocked the ability of FasL to induce loss of mitochondrial transmembrane potential (Δγm), suggesting that MKP-1 acts upstream of mitochondrial pro-apoptotic events induced by FasL and that the SAPK/JNK pathway may form the signaling link between Fas receptor and mitochondrial dysfunction. Thus, MKP-1 overexpression in prostate cancer may play a role in promoting prostate carcinogenesis by inhibiting FasL-induced cell death.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006980326855
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  • 4
    Electronic Resource
    Electronic Resource
    Poly(ADP-ribosylation) and apoptosis (1999)
    Springer
    Molecular and cellular biochemistry 199 (1999), S. 125-137 
    Details
    ISSN: 1573-4919
    Keywords: apoptosis ; ADP-ribosylation ; caspases ; PARP ; PARG
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Poly(ADP-ribosylation) is a post-translational modification playing a relevant role in DNA damage recovery, DNA replication and viral integration. Several reports also suggest a modulation of this process during cell death by apoptosis. The aim of this review is to discuss the possible involvement of poly(ADP-ribosylation) during apoptosis, by dealing with general considerations on apoptosis, and further examining the correlation between NAD consumption and cell death, the regulation of poly(ADP-ribose) metabolism in apoptotic cells, the effect of poly(ADP-ribose) polymerase inhibition on cell death occurrence and the use of enzyme cleavage as a marker of apoptosis. Finally, the future prospects of the research in this area will be addressed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006962716377
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  • 5
    Electronic Resource
    Electronic Resource
    A dual approach in the study of poly (ADP-ribose) polymerase: In vitro random mutagenesis and generation of deficient mice (1999)
    Springer
    Molecular and cellular biochemistry 193 (1999), S. 53-60 
    Details
    ISSN: 1573-4919
    Keywords: DNA binding protein ; NAD metabolism ; cellular response to DNA damage ; γ-rays ; alkylating agents ; genomic instability ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract A dual approach to the study of poly (ADP-ribose)polymerase (PARP) in terms of its structure and function has been developed in our laboratory. Random mutagenesis of the DNA binding domain and catalytic domain of the human PARP, has allowed us to identify residues that are crucial for its enzymatic activity. In parallel PARP knock-out mice were generated by inactivation of both alleles by gene targeting. We showed that: (i) they are exquisitely sensitive to γ-irradiation, (ii) they died rapidly from acute radiation toxicity to the small intestine, (iii) they displayed a high genomic instability to γ-irradiation and MNU injection and, (iv) bone marrow cells rapidly underwent apoptosis following MNU treatment, demonstrating that PARP is a survival factor playing an essential and positive role during DNA damage recovery and survival.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006947707713
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  • 6
    Electronic Resource
    Electronic Resource
    Involvement of PARP and poly(ADP-ribosyl)ation in the early stages of apoptosis and DNA replication (1999)
    Springer
    Molecular and cellular biochemistry 193 (1999), S. 137-148 
    Details
    ISSN: 1573-4919
    Keywords: PARP ; poly(ADP-ribosyl)ation ; apoptosis ; DNA replication
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract We have focused on the roles of PARP and poly(ADP-ribosyl)ation early in apoptosis, as well as during the early stages of differentiation-linked DNA replication. In both nuclear processes, a transient burst of PAR synthesis and PARP expression occurs early, prior to internucleosomal DNA cleavage before commitment to apoptosis as well as at the round of DNA replication prior to the onset of terminal differentiation. In intact human osteosarcoma cells undergoing spontaneous apoptosis, both PARP and PAR decreased after this early peak, concomitant with the inactivation and cleavage of PARP by caspase-3 and the onset of substantial DNA and nuclear fragmentation. Whereas 3T3-L1, osteosarcoma cells, and immortalized PARP +/+ fibroblasts exhibited this early burst of PAR synthesis during Fas-mediated apoptosis, neither PARP-depleted 3T3-L1 PARP-antisense cells nor PARP -/- fibroblasts showed this response. Consequently, whereas control cells progressed into apoptosis, as indicated by induction of caspase-3-like PARP-cleavage activity, PARP-antisense cells and PARP -/- fibroblasts did not, indicating a requirement for PARP and poly(ADP-ribosyl)ation of nuclear proteins at an early reversible stage of apoptosis. In parallel experiments, a transient increase in PARP expression and activity were also noted in 3T3-L1 preadipocytes 24 h after induction of differentiation, a stage at which ~95% of the cells were in S-phase, but not in PARP-depleted antisense cells, which were consequently unable to complete the round of DNA replication required for differentiation. PARP, a component of the multiprotein DNA replication complex (MRC) that catalyzes viral DNA replication in vitro, poly(ADP-ribosyl)ates 15 of ~40 MRC proteins, including DNA pol α, DNA topo I, and PCNA. Depletion of endogenous PARP by antisense RNA expression in 3T3-L1 cells results in MRCs devoid of any DNA pol α and DNA pol δ activities. Surprisingly, there was no new expression of PCNA and DNA pol α, as well as the transcription factor E2F-1 in PARP-antisense cells during entry into S-phase, suggesting that PARP may play a role in the expression of these proteins, perhaps by interacting with a site in the promoters for these genes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006988832729
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  • 7
    Electronic Resource
    Electronic Resource
    Bcl-2, survivin and variant CD44 v7-v10 are downregulated and p53 is upregulated in breast cancer cells by progesterone: Inhibition of cell growth and induction of apoptosis (1999)
    Springer
    Molecular and cellular biochemistry 202 (1999), S. 53-61 
    Details
    ISSN: 1573-4919
    Keywords: breast cancer cells ; anti-apoptotic genes ; apoptosis ; progesterone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Progesterone inhibits the proliferation of normal breast epithelial cells in vivo, as well as breast cancer cells in vitro. But the biologic mechanism of this inhibition remains to be determined. We explored the possibility that an antiproliferative activity of progesterone in breast cancer cell lines is due to its ability to induce apoptosis. Since p53, bcl-2 and survivin genetically control the apoptotic process, we investigated whether or not these genes could be involved in the progesterone-induced apoptosis. We found a maximal 90% inhibition of cell proliferation with T47-D breast cancer cells after exposure to 10 μM progesterone for 72 h. Control progesterone receptor negative MDA-231 cancer cells were unresponsive to 10 μM progesterone. The earliest sign of apoptosis is translocation of phosphatidylserine from the inner to the outer leaflet of the plasma membrane and can be monitored by the calcium-dependent binding of annexin V in conjunction with flow cytometry. After 24 h of exposure to 10 μM progesterone, cytofluorometric analysis of T47-D breast cancer cells indicated 43% were annexin V-positive and had undergone apoptosis and no cells showed signs of cellular necrosis (propidium iodide negative). After 72 h of exposure to 10 μM progesterone, 48% of the cells had undergone apoptosis and 40% were annexin V positive/propidium iodide positive indicating signs of necrosis. Control untreated cancer cells did not undergo apoptosis. Evidence proving apoptosis was also demonstrated by fragmentation of nuclear DNA into multiples of oligonucleosomal fragments. After 24 h of exposure of T47-D cells to either 1 or 10 μM progesterone, we observed a marked down-regulation of protooncogene bcl-2 protein and mRNA levels. mRNA levels of survivin and the metastatic variant CD44 v7-v10 were also downregulated. Progesterone increased p53 mRNA levels. These results demonstrate that progesterone at relative high physiological concentrations, but comparable to those seen in plasma during the third trimester of human pregnancy, exhibited a strong antiproliferative effect on breast cancer cells and induced apoptosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007081021483
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  • 8
    Electronic Resource
    Electronic Resource
    Role of nitric oxide in the induction of apoptosis by smokeless tobacco extract (1999)
    Springer
    Molecular and cellular biochemistry 200 (1999), S. 51-57 
    Details
    ISSN: 1573-4919
    Keywords: smokeless tobacco ; apoptosis ; nitric oxide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Smokeless tobacco usage is, a growing public health concern in the United States. Lesions of the oral cavity have been clearly linked to smokeless tobacco use. The objective of this study was to determine the biochemical effects of smokeless tobacco extract (STE) exposure upon hamster cheek pouch cell (HCPC-1) cultures. HCPC-1 cells were exposed to a 5 -fold dose-range of STE (0.5, 1.0 and 2.5%) over a time-course of 24-96 h. Following each exposure we measured various biochemical parameters of cell proliferation and cell death. Cell viability, cell cycle progression and S-phase DNA synthesis were measured as markers of cell proliferation. We measured lactate dehydrogenase leakage as a marker of cell membrane damage and cell death due to necrosis. No significant alterations were observed in cell cycle progression and cell proliferation as a result of exposure to STE. LDH measured colorimetrically indicated no significant effect with the lower doses (0.5, 1.0 and 2.5% STE). Apoptosis measured as the A0 peak and by the TUNEL procedure revealed that STE caused significant rates of apoptosis. Maximal apoptosis was noted between 48-96 h. In order to probe the mechanism further we measured the levels of nitrites as an indicator of nitric oxide (NO) in the media. NO levels were significantly elevated at the doses that caused an induction of apoptosis. The results from this study indicate that STE causes a dose-dependent induction of apoptosis and that this is mediated by nitric oxide.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006985700851
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  • 9
    Electronic Resource
    Electronic Resource
    Clostridial toxins: Molecular probes of Rho-dependent signaling and apoptosis (1999)
    Springer
    Molecular and cellular biochemistry 193 (1999), S. 37-42 
    Details
    ISSN: 1573-4919
    Keywords: Rho ; GTPase ; toxins ; Clostridium ; signal transduction ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The Rho family small GTPases are members of the Ras superfamily of small GTPases. Rho proteins were first determined to act as key regulators of many types of actin cytoskeletal-dependent cellular functions. Recent work by several investigators indicates that Rho GTPases are also critical modulators of several important intracellular and nuclear signal transduction pathways. Certain clostridial toxins and exoenzymes covalently modify, and thereby inactivate, specific types of Rho family GTPases. As such, these microbial enzymes have proven invaluable in helping to identify structural and functional attributes of Rho GTPases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006939505896
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  • 10
    Electronic Resource
    Electronic Resource
    Functional analysis of poly(ADP-ribose) polymerase in Drosophila melanogaster (1999)
    Springer
    Molecular and cellular biochemistry 193 (1999), S. 103-108 
    Details
    ISSN: 1573-4919
    Keywords: Poly(ADP-ribose) polymerase ; Drosophila melanogaster ; alternative splicing ; apoptosis ; DNA repair ; development
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Poly(ADP-ribose) polymerase (PARP) is conserved in eukaryotes. To analyze the function of PARP, we isolated and characterized the gene for PARP in Drosophila melanogaster. The PARP gene consisted of six translatable exons and spanned more than 50 kb. The DNA binding domain is encoded by exons 1-4. Although the consensus cleavage site of CED-3 like protease during apoptosis is conserved from human to Xenopus laevis PARPs, it is neither conserved in the corresponding region of Drosophila nor Sarcophaga peregrina. There are two cDNAs species in Drosophila. One cDNA could encode the full length PARP protein (PARP I), while the other is a truncated cDNA which could encode a partial-length PARP protein (PARP II), which lacks the automodification domain and is possibly produced by alternative splicing. The expression of these two forms of PARP in E. coli demonstrated that while PARP II has the catalytic NAD-binding domain and DNA-binding domain it is enzymatically inactive. On the other hand PARP I is active. A deletion mutant of PARP gene could grow to the end of embryogenesis but did not grow to the adult fly. These results suggest that the PARP gene plays an important function during the development of Drosophila.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006920429095
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  • 11
    Electronic Resource
    Electronic Resource
    Newly discovered anti-inflammatory properties of the benzamides and nicotinamides (1999)
    Springer
    Molecular and cellular biochemistry 193 (1999), S. 119-125 
    Details
    ISSN: 1573-4919
    Keywords: benzamides ; nicotinamides ; apoptosis ; inflammation ; NF-kB ; DNA repair
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Our laboratory has concentrated on the possible regulation the benzamides and nicotinamides may have on the processes of DNA repair and apoptosis. Recent reports [14-16] have suggested that both apoptosis and inflammation are regulated by the transcription factor NF-kB. We have initiated studies regarding the hypothesis that the benzamides and nicotinamides could inhibit the production of tumor necrosis factor alpha (TNFalpha) and the inflammatory response as well as induce apoptosis via inhibition of NF-kB. Our data have shown that nicotinamide and two N-substituted benzamides, metoclopramide (MCA) and 3-chloroprocainamide (3-CPA), gave dose dependent inhibition of lipopolysacharide induced TNFalpha in the mouse within the dose range of 10-500 mg/kg. Moreover, lung edema was prevented in the rat by 3 ï 50 mg/kg doses of 3-CPA or MCA, and 100-200 μM doses of MCA could also inhibit NF-kB in Hela cells. Taken together these data strongly support the notion that benzamides and nicotinamides have potent anti-inflammatory and antitumor properties, because their primary mechanism of action is regulated by inhibition at the gene transcription level of NF-kB, which in turn inhibits TNFalpha and induces apoptosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006932714982
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  • 12
    Electronic Resource
    Electronic Resource
    Growth arrest and induction of apoptosis in breast cancer cells by antisense depletion of protein kinase A-RIα subunit: p53-independent mechanism of action (1999)
    Springer
    Molecular and cellular biochemistry 195 (1999), S. 25-36 
    Details
    ISSN: 1573-4919
    Keywords: antisense oligonucleotide ; apoptosis ; cAMP-dependent protein kinase ; cancer cells ; growth inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The enhanced expression of the RIα subunit of cyclic AMP-dependent protein kinase type 1 (PKA-I) has been correlated with cancer cell growth. We have investigated the effects of sequence-specific inhibition of RIα gene expression on the growth of MCF-7 human breast cancer cells. We report that RIα antisense treatment results in a reduction in RIα expression at both mRNA and protein levels and inhibition of cell growth. The growth inhibition was accompanied by changes in cell morphology, cleavage of poly(ADP-ribose) polymerase (PARP) and appearance of apoptotic nuclei. In addition, bcl-2 protein level was reduced and p53 expression increased in growth arrested cells. Interestingly, RIα antisense inhibited cell viability and induced apoptosis in the absence of p53, suggesting that these actions of RIα antisense are exerted independent of p53. In contrast, two- and four-base mismatched control oligonucleotides had no effect on either cell growth or morphology. These results demonstrate that the RIα antisense, which efficiently depletes the growth stimulatory molecule RIα, induces cell differentiation and apoptosis, providing a new approach to combat breast cancer cell growth.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006990231186
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  • 13
    Electronic Resource
    Electronic Resource
    TNF-α induced altered signaling mechanism in human neutrophil (1999)
    Springer
    Molecular and cellular biochemistry 197 (1999), S. 97-108 
    Details
    ISSN: 1573-4919
    Keywords: neutrophil ; PKC ; TNF-α ; apoptosis ; DNA fragmentation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract In the present study we investigated the TNF-α induced signal transduction mechanism in human neutrophil. Exogenously added TNF-α affects both PKC activity and its translocation from cytosol to the membrane. Endogenous protein phosphorylation pattern is inhibited in TNF-α induced neutrophil in Ca-dependent and Ca-independent manner, including a major 47 and 66 kDa cytosolic proteins, which may be implicated in superoxide anion generation. However TNF-α dose dependently enhances the expression of ζ-PKC isotype but not the β-PKC. Morphology and cell cytotoxicity are studied in TNF-α treated neutrophil to understand the TNF-α induced cell death or apoptosis and these experiment is further confirmed by DNA fragmentation analysis. These results clearly demonstrate that TNF-α induces cellular death of human neutrophil at least in part by enhanced expression of Ca-independent ζ-PKC. These observations provide an insight towards understanding the function of ζ-PKC in apoptotic pathway.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006935114624
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  • 14
    Electronic Resource
    Electronic Resource
    Diminished energy metabolism and enhanced apoptosis in livers of B6C3F1 mice treated with the antihepatocarcinogen rotenone (1999)
    Springer
    Molecular and cellular biochemistry 201 (1999), S. 25-32 
    Details
    ISSN: 1573-4919
    Keywords: rotenone ; apoptosis ; oncogenes ; liver cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Rotenone decreases the incidence of hepatocellular carcinoma and lowers rates of hepatocellular proliferation. In an effort to delineate mechanisms involved, the in vivo effect of rotenone on liver mitochondrial metabolism, apoptotic machinery as well as elements of the hepatic signal transduction pathways were investigated. Mitochondria from livers of male B6C3F1 mice fed a standard diet containing 600 ppm rotenone for 7 days were uncoupled or inhibited when succinate or glutamate plus malate were used as the substrate, respectively. These livers also showed a significant increase in apoptosis compared with control livers. Furthermore, rotenone increased the expression of c-myc mRNA to 5-fold of control values within 3 days, an effect which was still observed (3-fold) after 7 days. Levels of p53 mRNA were also increased 3-fold after 1 day, but declined to control levels by 7 days. Rotenone also caused a transient, yet marked increase in liver particulate glyceraldehyde phosphate dehydrogenase (GAPDH) protein expression, while it did not alter the expression of the cytosolic form of the enzyme. Conversely, mRNA of the proto-oncogene H-ras showed a decline of 35% after 3 days of rotenone treatment, and remained diminished for the duration of the experiment. These data suggest that rotenone may act as an anticancer agent by diminishing mitochondrial bioenergetics which prevents basal hepatocyte proliferation and lowers the threshold for liver cells with DNA damage to undergo apoptosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007024905046
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  • 15
    Electronic Resource
    Electronic Resource
    Preparative High-Resolution Two-Dimensional Electrophoresis Enables the Identification of RNA Polymerase B Transcription Factor 3 as an Apoptosis-Associated Protein in the Human BL60–2 Burkitt Lymphoma Cell Line (1999)
    Springer
    The protein journal 18 (1999), S. 225-231 
    Details
    ISSN: 1573-4943
    Keywords: Two-dimensional electrophoresis ; MALDI-MS ; apoptosis ; RNA polymerase B transcription factor 3
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Apoptosis or programmed cell death is essential in the process of controlling lymphocyte growth and selection. We identified RNA polymerase B transcription factor 3 (BTF3), which is associated with anti-IgM antibody-mediated apoptosis, using a subclone of the human Burkitt lymphoma cell line BL60. To identify the transcription factor BTF3, which is expressed only in minor amounts, we used preparative high-resolution two-dimensional gel electrophoresis (2DE) employing carrier ampholytes for isoelectric focusing. Comparison of the 2DE protein patterns from apoptotic and nonapoptotic cells showed BTF3 as a predominantly altered protein spot. The characterization of the differentially expressed transcription factor and 13 marker proteins described in this study were performed by internal Edman microsequencing and/or by peptide mass fingerprinting using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). The proteome analysis was significantly improved by performing the newly developed preparative high-resolution two-dimensional gels employing high protein concentrations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020636308270
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  • 16
    Electronic Resource
    Electronic Resource
    Protein Kinase C Targeting in Antineoplastic Treatment Strategies (1999)
    Springer
    Investigational new drugs 17 (1999), S. 227-240 
    Details
    ISSN: 1573-0646
    Keywords: apoptosis ; protein kinase C ; sphingoid bases ; safingol ; diglyceride ; bryostatin 1 ; staurosporine ; 7-hydroxy staurosporine (UCN-01) ; 4′-N-benzoyl staurosporine (CGP-41251) ; calphostin C (UCN-1028c)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Neoplastic cell survival is governed by a balance between pro-apoptotic and anti-apoptotic signals. Noteworthy among several anti-apoptotic signaling elements is the protein kinase C (PKC) isoenzyme family, which mediates a central cytoprotective effect in the regulation of cell survival. Activation of PKC, and subsequent recruitment of numerous downstream elements such as the mitogen-activated protein kinase (MAPK) cascade, opposes initiation of the apoptotic cell death program by diverse cytotoxic stimuli. The understanding that the lethal actions of numerous antineoplastic agents are, in many instances, antagonized by cytoprotective signaling systems has been an important stimulus for the development of novel antineoplastic strategies. In this regard, inhibition of PKC, which has been shown to initiate apoptosis in a variety of malignant cell types, has recently been the focus of intense interest. Furthermore, there is accumulating evidence that selective targeting of PKC may prove useful in improving the therapeutic efficacy of established antineoplastic agents. Such chemosensitizing strategies can involve either (a) direct inhibition of PKC (e.g., following acute treatment with relatively specific inhibitors such as the synthetic sphingoid base analog safingol, or the novel staurosporine derivatives UCN-01 and CGP-41251) or (b) down-regulation (e.g., following chronic treatment with the non-tumor-promoting PKC activator bryostatin 1). In preclinical model systems, suppression of the cytoprotective function(s) of PKC potentiates the activity of cytotoxic agents (e.g., cytarabine) as well as ionizing radiation, and efforts to translate these findings into the clinical arena in humans are currently underway. Although the PKC-driven cytoprotective signaling systems affected by these treatments have not been definitively characterized, interference with PKC activity has been associated with loss of the mitogen-activated protein kinase (MAPK) response. Accordingly, recent pre-clinical studies have demonstrated that pharmacological disruption of the primary MEK-ERK module can mimic the chemopotentiating and radiopotentiating actions of PKC inhibition and/or down-regulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006328303451
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  • 17
    Electronic Resource
    Electronic Resource
    Activation-Induced Apoptosis of Peripheral Lymphocytes Treated with 7-Hydroxystaurosporine, UCN-01 (1999)
    Springer
    Investigational new drugs 17 (1999), S. 335-341 
    Details
    ISSN: 1573-0646
    Keywords: UCN-01 ; IL-2 receptor ; Fas ; Fas-ligand ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract 7-hydroxystaurosporine (UCN-01) is a new anticancer agentwhich exerts an inhibitory effect on cell cycle check points andis currently under phase I clinical trials in US and Japan.Preliminary clinical data indicated that UCN-01 remained inplasma at high concentrations for long periods of time. Thisunavoidable high plasma drug exposure is likely to lead tohematological toxicities in patients. In the present study,cultured human peripheral blood lymphocytes (PBLs) were used toevaluate the possible hematological toxicities of UCN-01treatment. UCN-01 induces apoptosis, and the induction ofapoptosis-related surface markers were also examined toinvestigate the involvement of these molecules in UCN-01-inducedapoptosis in PBLs. in vitroviability of PBLs wasdecreased by high dose of UCN-01 (25 μM, 3-day exposure). Thiseffect of UCN-01 was significantly suppressed by the presence ofhuman serum, suggesting that some specific inhibitory factor(s)in human serum may antagonize the lympholytic effect of UCN-01.The percentage of annexin V-positive PI-negative cells increasedwith exposure to UCN-01 in a time- and dose-dependent manner; byup to 30.3% after exposure to 25 μM UCN-01 for 3 days.At the same time, the expression of both interleukin-2 receptor(IL-2R, CD25) and Fas (CD95), analyzed by flow cytometry, wasinduced. Con A-stimulated PBLs were more sensitive toUCN-01-induced apoptosis than non-stimulated lymphocytes andUCN-01 increased the sFas-L released into culture medium from conA-stimulated PBLs. Therefore, lymphocyte depletion mediated byactivation-induced apoptosis is likely to occur in patientstreated with UCN-01 at high doses.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006374118879
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  • 18
    Electronic Resource
    Electronic Resource
    Verotoxin/Globotriaosyl Ceramide Recognition: Angiopathy, Angiogenesis and Antineoplasia (1999)
    Springer
    Bioscience reports 19 (1999), S. 345-354 
    Details
    ISSN: 1573-4935
    Keywords: Glycolipid ; apoptosis ; intracellular traffic ; multidrug resistance ; ovarian carcinoma ; astrocytoma ; post transplant lymphoproliferative disease ; bone marrow purging
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Verotoxin (VT) is involved in the etiology of both hemorrhagic colitis and the hemolytic uremic syndrome which are microvasculopathies of the colon and pediatric renal glomerulus respectively. Thus, VT can be considered a vasotoxin. Cell sensitivity in vitro varies according to the receptor glycolipid (globotriaosyl ceramide-Gb3) expression and also to intracellular trafficking of the receptor/toxin complex, such that in highly sensitive cells, the toxin is targeted to the endoplasmic reticulum and nuclear envelope. Such cells include tumor cells which have become drug resistant. Thus Gb3 is upregulated in certain tumors and when such tumor cells become drug resistant, their sensitivity to verotoxin increases. This may be due to a direct role of the MDR1 drug efflux pump in glycolipid biosynthesis. In addition to the tumor tissue, the toxin receptor may also be expressed in the tumor neovasculature suggesting that activated endothelial cells may be verotoxin sensitive. Thus VT may have both a direct and indirect antineoplastic potential. VT has proved highly effective in a xenograft cancer model and the possible therapeutic use of VT is discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020299819637
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  • 19
    Electronic Resource
    Electronic Resource
    Ceramide Glycanase Activities in Human Cancer Cells (1999)
    Springer
    Bioscience reports 19 (1999), S. 449-460 
    Details
    ISSN: 1573-4935
    Keywords: ceramide glycanase ; cancer cells ; glycosphingolipid ; sphingosine ; ceramide ; apoptosis ; PPMP ; PDMP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Ceramide glycanase (CGase) activities have been detected in different human tumor cells (colon, carcinoma Colo-205; neuroblastoma, IMR-32; breast cancer lines, SKBr3 and MCF7). However, the level of enzymatic activity is lower in these cells compared to that present in other mammalian tissues reported before (Basu, M., Kelly, P., Girzadas, M. A., Li, Z., and Basu, S. Methods Enzymol. (in press)). The majority of CGase activity was found in the 100,000g soluble supernatant fraction isolated from all these cell lines and tissues. Using the soluble enzyme, the requirement for optimum CGase activity was found to be consistent with previous observations found for rat and rabbit tissues (Basu, M., Dastgheib, S., Girzadas, M. A., O'Donnell, P. H., Westervelt, C. W., Li, Z., Inokuchi, J. I., and Basu, S. (1998) Acta Pol. Biochim. 42:327). The CGase activities from both Colo-205 and IMR-32 cells are optimum at a protein to detergent ratio of one. All the mammalian CGases, including human cancer cells, show an optimum pH between 5.5 and 5.8 in sodium acetate buffer. The CGase activities from cancer cells are found to be cation-independent; however, mercury, zinc, and copper ions seem to inhibit the enzyme activity substantially in both tumor cells lines. The mercury ion inhibition of CGase activities from all different sources indicates a possible structural homology in the CGase proteins. Radiolabeled substrates, labeled at the sphingosine double bond or at the 3-position of sphingosine without modifying double bond of sphingosine were used in this investigation. Both were active substrates with all enzyme preparations isolated from different cancer cells (apparent Km, 500 μM for nLcOse5[3H-DT]Cer and 350 μM for GgOse4[sph-3-3H]Cer with Colo-205 enzyme). Structural analogues of ceramide and sphingosine (L-PPMP, L-PDMP, alkylamines, and Tamoxifen) inhibited cancer cell CGase activities in vitro.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020220524180
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  • 20
    Electronic Resource
    Electronic Resource
    Pharmacodynamics and Toxicodynamics of Drug Action: Signaling in Cell Survival and Cell Death (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 790-798 
    Details
    ISSN: 1573-904X
    Keywords: MAPK ; caspases ; chemopreventive agents ; phase II drug metabolizing enzymes ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In therapeutic response to drugs, the plasma concentration range leads to the establishment of a safe and effective dosage regimen. Our hypothesis is that by studying drug concentration-dependent effect on signal transduction mechanisms, a better understanding of the beneficial pharmacodynamic and adverse toxicodynamic responses elicited by the drug may be achieved. Using two classes of chemopreventive compounds (phenolic antioxidants and isothiocyanates), we illustrate the potential utility of two signal transduction pathways elicited by these agents to predict the pharmacodynamic effect (induction of Phase II drug metabolizing enzymes) and the potential toxicodynamic response (stimulation of caspase activity and cytotoxic cell death). At lower concentration, phenolic antioxidants and isothiocyanates activate mitogen-activated protein kinase (MAPK; extracellular signal-regulated protein kinase 2, ERK2; and c-Jun N-terminal kinase 1, JNK1) in a concentration-and time-dependent manner. The activation of MAPK by these compounds may lead to the induction of cell survival/protection genes such as c-jun, c-fos, or Phase II drug metabolizing enzymes. However, at higher concentrations, these agents activate another signaling molecule, ICE/Ced3 cysteine protease enzymes (caspases) leading to apoptotic cell death. The activation of these pathways may dictate the fate of the cells/tissues upon exposure to drugs or chemicals. At lower concentrations, these compounds activate MAPK leading to the induction of Phase II genes, which may protect the cells/tissues against toxic insults and therefore may enhance cell survival. On the other hand, at higher concentrations, these agents may activate the caspases, which may lead to apoptotic cell death, and have toxicity. Understanding the activation of these and other signal transduction events elicited by various drugs and chemicals may yield insights into the regulation of gene expression of drug metabolizing enzymes and cytotoxicity. Thus, the study of signaling events in cell survival (hemeostasis) and cell death (cytotoxicity) may have practical application during pharmaceutical drug development.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011953431486
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  • 21
    Electronic Resource
    Electronic Resource
    Mitochondrial Events in the Life and Death of Animal Cells: A Brief Overview (1999)
    Springer
    Journal of bioenergetics and biomembranes 31 (1999), S. 291-304 
    Details
    ISSN: 1573-6881
    Keywords: Cell death ; aging ; necrosis ; apoptosis ; mitochondria ; oxidative phosphorylation ; electron transport chain ; ATP synthase ; cytochrome c ; mitochondrial DNA ; reactive oxygen species (ROS)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Physics
    Notes: Abstract Traditionally, mitochondria have been viewed as the “powerhouse” of the cell, i.e., the site of theoxidative phosphorylation machinery involved in ATP production. Consequently, much of theresearch conducted on mitochondria over the past 4 decades has focused on elucidating both thosemolecular events involved in ATP synthesis by oxidative phosphorylation and those involved inthe biogenesis of the oxidative phosphorylation machinery. While monumental achievements havebeen made, and continue to be made, in the study of these remarkable but extremely complexprocesses essential for the life of most animal cells, it has been only in recent years that a largebody of biological and biomedical scientists have come to recognize that mitochondria participatein other important processes. Two of these are cell death and aging which, not surprisingly, are relatedprocesses both involving, in part, the oxidative phosphorylation machinery. This new awareness hassparked a new and growing area of mitochondrial research, that has become of great interest to awide variety of scientists ranging from those involved in elucidating the role of mitochondria incell death and aging to those interested in either suppressing or facilitating these processes as itrelates to identifying new therapies or drugs for human disease. It is the purpose of this briefintroductory review to provide an overview of those mitochondrial events involved in the life anddeath of animal cells and to indicate how these events might relate to the human aging process.Much more is known, much remains controversial, and even more remains to be learned as indicatedin the excellent set of minireviews that follow.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005453700533
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  • 22
    Electronic Resource
    Electronic Resource
    Mitochondria at the Crossroad of Apoptotic Cell Death (1999)
    Springer
    Journal of bioenergetics and biomembranes 31 (1999), S. 321-326 
    Details
    ISSN: 1573-6881
    Keywords: Mitochondria ; apoptosis ; caspases ; cytochrome c ; Fas ; bcl-2
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Physics
    Notes: Abstract In the past few years, it has become widely appreciated that apoptotic cell death generallyinvolves activation of a family of proteases, the caspases, which undermine the integrity ofthe cell by cleavage of critical intracellular substrates. Caspases, which are synthesized asinactive zymogens, are themselves caspase substrates and this cleavage leads to their activation.Hence, the potential exists for cascades of caspases leading to cell death. However, it has beenrecently recognized that another, perhaps more prominent route to caspase activation, involvesthe mitochondria. Upon receipt of apoptotic stimuli, either externally or internally generated,cells initiate signaling pathways which converge upon the mitochondria to promote release ofcytochrome C to the cytoplasm; cytochrome c, thus released, acts as a potent cofactor incaspase activation. Even cell surface “death receptors” such as Fas, which can trigger directcaspase activation (and potentially a caspase cascade), appear to utilize mitochondria as partof an amplification mechanism; it has been recently demonstrated that activated caspases cancleave key substrates to trigger mitochondrial release of cytochrome c, thereby inducing furthercaspase activation and amplifying the apoptotic signal. Therefore, mitochondria play a centralrole in apoptotic cell death, serving as a repository for cytochrome c.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005471701441
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  • 23
    Electronic Resource
    Electronic Resource
    Mitochondrial Uncoupling: Role of Uncoupling Protein Anion Carriers and Relationship to Thermogenesis and Weight Control “The Benefits of Losing Control” (1999)
    Springer
    Journal of bioenergetics and biomembranes 31 (1999), S. 493-506 
    Details
    ISSN: 1573-6881
    Keywords: Energy expenditure ; reactive oxygen species ; cellular viability ; apoptosis ; necrosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Physics
    Notes: Abstract Uncoupling proteins, a subgroup of the mitochondrial anion transporter superfamily, have beenidentified in prokaryotes, plants, and mammalian cells. Evolutionary conservation of thesemolecules reflects their importance as regulators of two critical mitochondrial functions, i.e.,ATP synthesis and the production of reactive oxygen species (ROS). Although the amino acidsequences of the three mammalian uncoupling proteins, UCP1, UCP2 and UCP3, are verysimilar, each homolog is the product of a unique gene and important differences have beendemonstrated in their tissue-specific expression and regulation. UCP1 and UCP3 appear to bekey regulators of energy expenditure, and hence, nonshivering thermogenesis, either in brownadipose tissue (UCP1) or skeletal muscle (UCP3). UCP2 is expressed more ubiquitously,although generally at low levels, in many tissues. There is conflicting evidence about itsimportance as a regulator of resting metabolic rate. However, evidence suggests that thishomolog might modulate the mitochondrial generation of ROS in some cell types, includingmacrophages and hepatocytes. While the induction of various uncoupling protein homologsprovides adaptive advantages, both to the organism (e.g., thermogenesis) and to individual cells(e.g., reduced ROS), increased uncoupling protein activity also increases cellular vulnerability tonecrosis by compromising the mitochondrial membrane potential. This narrow “risk—benefit”margin necessitates tight control of uncoupling protein activity in order to preserve cellularviability and much remains to be learned about the regulatory mechanisms involved.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005452624640
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  • 24
    Electronic Resource
    Electronic Resource
    A Novel Podophyllotoxin-Derived Compound GL331 Is More Potent than Its Congener VP-16 in Killing Refractory Cancer Cells (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 997-1002 
    Details
    ISSN: 1573-904X
    Keywords: GL331 ; VP-16 ; apoptosis ; cytotoxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. GL331 is a new homolog of VP-16, and has demonstrated more efficacious anti-cancer activity in both the in vitro and in vivo lymphoma systems. To extensively explore GL331's clinical value, we furthermore evaluate the cytotoxicity and apoptosis-inducing activity of GL331 in several human cell lines from cancers that are not normally treated with VP-16. Methods. By MTT and clonogenic survival assays, the cytotoxicities of GL331 and VP-16 were evaluated in a variety of cell lines including nasopharyngeal, hepatocellular, gastric, colon, cervical, and neuro-blastoma cancer types. Western blot analysis was performed to detect the MDR-1 level in these cell lines. By Annexin V-staining flow cytometry and detection of DNA ladders, the apoptosis-inducing activities of GL331 and VP-16 were also evaluated. Results. GL331 showed more efficacy than its congener VP-16 in killing cancer cells. The estimated ID50 of GL331 were 2.5 to 17-fold lower than those of VP-16. GL331 possessed more cell-killing activity even in MDR-1-overexpressing cell lines such as HCC36 and SW620. Its higher cytotoxicity could be attributed by the elevated ability to induce apoptotic cell death. Conclusions. GL331's overriding drug resistance and higher cancer cell-killing activity suggest its superiority in clinical cancer therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018971313256
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  • 25
    Electronic Resource
    Electronic Resource
    Effects of Arbekacin and Vancomycin on Release of Lactate Dehydrogenase and Fragmentation of DNA in LLC-PK1 Kidney Epithelial Cells (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1132-1135 
    Details
    ISSN: 1573-904X
    Keywords: arbekacin ; vancomycin ; cisplatin ; apoptosis ; toxicity ; LLC-PK1 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011919306412
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  • 26
    Electronic Resource
    Electronic Resource
    New antitumor leads from a peptidomimetic library (1999)
    Springer
    International journal of peptide research and therapeutics 6 (1999), S. 325-333 
    Details
    ISSN: 1573-3904
    Keywords: antiproliferative effect ; apoptosis ; combinatorial library ; isosteric structures ; oxaniloyl hydrazides ; peptidomimetics ; substrate-binding site ; tyrosine kinase inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A parallel combinatorial library of over 1600 compounds has been designed and synthesized for the development of new potential peptidomimetic protein tyrosine kinase (PTK) inhibitor leads. These peptidomimetic molecules are aimed at intervening with the substrate binding site of the pp60c-src enzyme. The new structures were based on known PTK inhibitors with at least two variously substituted aromatic moieties attached by spacer groups of different length and flexibility. Eleven bis-aryl-type inhibitory compounds were found in the range of 18–100 μM IC50 concentrations from combinations of 12 different substituents. Molecular modeling of the active compounds showed a characteristic distance of 12–14 Å between the farthest sp2 carbon atoms of the two aromatic rings. Conformational analysis of several peptide substrates recently found for pp60c-src PTK showed that the energy-minimized conformers had the same distance between the two aromatic moieties. Several compounds in the library not only showed remarkable PTK inhibitory activity but also a significant apoptosis-inducing effect on HT-29 human colon tumor cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008994116275
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  • 27
    Electronic Resource
    Electronic Resource
    New antitumor leads from a peptidomimetic library (1999)
    Springer
    International journal of peptide research and therapeutics 6 (1999), S. 325-333 
    Details
    ISSN: 1573-3904
    Keywords: antiproliferative effect ; apoptosis ; combinatorial library ; isosteric structures ; oxaniloyl hydrazides ; peptidomimetics ; substrate-binding site ; tyrosine kinase inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary A parallel combinatorial library of over 1600 compounds has been designed and synthesized for the development of new potential peptidomimetic protein tyrosine kinase (PTK) inhibitor leads. These peptidomimetic molecules are aimed at intervening with the substrate binding site of the pp60c−src enzyme. The new structures were based on kown PTK inhibtors with at least two variously substituted aromatic moieties attached by spacer groups of different length and flexibility. Eleven bis-aryl-type inhibitory compounds were found in the range of 18–100 μM IC50 concentrations from combinations of 12 different substituents. Molecular modeling of the active compounds showed a characteristic distance of 12–14 Å between the farthest sp2 carbon atoms of the two aromatic rings. Conformational analysis of several peptide substrates recently found for pp60c−src PTK showed that the energyminimized conformers had the same distance between the two aromatic moieties. Several compounds in the library not only showed remarkable PTK inhibitory activity but also a significant apoptosis-inducing effect on HT-29 human colon tumor cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02443428
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