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  • 2005-2009  (22)
  • 2000-2004  (6)
  • 1
    Call number: M 08.0124
    In: Aachener geowissenschaftliche Beiträge
    Type of Medium: Monograph available for loan
    Pages: II, 26 S.
    ISBN: 3861309645
    Series Statement: Aachener geowissenschaftliche Beiträge 43
    Location: Upper compact magazine
    Branch Library: GFZ Library
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  • 2
    Monograph available for loan
    Monograph available for loan
    Berlin [u.a.] : de Gruyter
    Call number: 9/M 04.0562
    Type of Medium: Monograph available for loan
    Pages: X, 325 S. , Ill., graph. Darst., Kt.
    Edition: 5. Aufl.
    ISBN: 3110176971
    Location: Reading room
    Branch Library: GFZ Library
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  • 3
    Publication Date: 2007-04-12
    Print ISSN: 0004-640X
    Electronic ISSN: 1572-946X
    Topics: Physics
    Published by Springer
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  • 4
    Publication Date: 2007-11-16
    Description: Background: The immunoconjugate, gemtuzumab ozogamicin (GO; Mylotarg™), consisting of an anti-CD33 antibody (hP67.6) and a toxic calicheamicin-γ1 derivative, has proven effective in some patients with AML, but its effectiveness is limited by drug efflux, in particular mediated by P-glycoprotein. GO exerts it toxic effect by calicheamicin-γ1-induced DNA damage, which is followed by either successful DNA repair or cell death. Heat-shock protein 90 (HSP90) interacts with numerous client proteins and guides folding, localization, and turnover of key regulators of cell growth, cell cycle, differentiation, and survival. Inhibition of HSP90, e.g. with 17-allylamino-17-demethoxygeldanamycin (17-AAG), increases degradation of such proteins and can interfere with oncogenic signaling pathways and may increase the sensitivity of tumor cells to DNA damage. In this study, we tested whether 17-AAG sensitizes human AML cell lines and primary AML cells to the cytotoxic effect of GO or calicheamicin-γ1, in vitro, thus potentially overcoming drug resistance. Methods: CD33+ human AML cell lines and primary blast cells from patients with AML were treated continuously with various concentrations of GO (doses given as calicheamicin dose-equivalent) or free calicheamicin-γ1 in the presence or absence 17-AAG (25–500 nM) for 3 days before cytotoxicity was determined by flow cytometry with propidium iodide (PI). Phosphorylation of histone H2AX as measure for DNA damage was quantified by flow cytometry after 4 hours of incubation with drugs. Results: Relatively non-toxic doses of 17-AAG significantly enhanced both GO- and calicheamicin-γ1-induced cytotoxicity in cell lines that do not express P-glycoprotein (Pgp), such as ML-1 and NB4 cells (ML-1: increase of PI+ cells from 7.22±1.16% [mean±SEM] to 27.87±3.85% at 0.01 ng/mL GO [p
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 5
    Publication Date: 2004-11-16
    Description: Background: Gemtuzumab ozogamicin (GO; Mylotarg™), a novel immunoconjugate used for treatment of acute myeloid leukemia (AML), contains the humanized anti-CD33 antibody (hP67.6) as a carrier to facilitate cellular uptake of the toxic calicheamicin derivative. However, little is known about the importance of the quantity of CD33 expression for GO-induced cytotoxicity, and it has been argued that cytotoxic effects of GO can be achieved in the absence of CD33 expression. In addition, neither the endocytic process by which CD33 delivers antibody to the cytosol, nor the necessity of CD33 endocytosis for GO-induced cytotoxicity, has been established. We therefore investigated the quantitative relationship between CD33 expression and GO-mediated cytotoxicity, and determined the requirement for CD33 internalization in GO-induced cytotoxicity by identifying and mutating the cytoplasmic domain motif(s) that control internalization of antibody-bound CD33. Methods: Murine myeloid 32D cells (devoid of CD33) and human myeloid OCI-AML3 and KG-1a cells (weakly CD33+) were transduced with a lentiviral vector expressing either wild-type or mutant CD33 as well as green fluorescent protein (GFP) at a multiplicity of infection (MOI) of 1–100. GFP-positive cells were sorted by flow cytometry, re-cultured, and further analyzed for CD33 expression, internalization of anti-CD33 antibody, and GO susceptibility. CD33 expression was quantified by immunofluorescence staining. Antibody uptake was quantified with a flow-cytometry-based assay, in which cells labeled with unconjugated hP67.6 were allowed to internalize in antibody-free medium for various periods of time, before second and third step reagents were used to measure hP67.6 that remained on the cell surface. To assess GO-induced cytotoxicity, cells were treated continuously with various concentrations of GO for 3 days (+ cyclosporine A in KG-1a sublines), and cytotoxicity then determined by flow cytometry with propidium iodide. Results: In all 3 cell lines, lentivirus-mediated transfer of wild-type CD33 yielded subpopulations of GFP-positive cells that showed a MOI-dependent increase in expression levels of cell surface CD33. Compared to parental cells, transduced cells were significantly more sensitive to GO. Importantly, GO-sensitivity increased in a MOI-dependent manner, i.e. in a direct correlation with the cell surface expression levels of CD33. We could easily detect internalization of antibody-bound CD33 in cells that were transduced with wild-type CD33. Internalization of hP67.6 was almost completely prevented in cells that expressed a CD33 construct in which the proximal CD33 cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM) was disrupted by introduction of point mutations (CD33/Y340F or CD33/L343A), whereas internalization was only partially prevented in cells that expressed a mutated distal ITIM (CD33/Y358F). In addition, disruption of the ITIMs not only prevented effective internalization of antibody-bound CD33, but also significantly reduced GO-induced cytotoxicity, when compared to cells expressing wild-type CD33 at matchable levels. Conclusion: These data imply a pivotal role of both the number of CD33 molecules expressed on the cell surface and the rate of internalization of CD33 following antibody binding for GO-induced cytotoxicity, and suggest novel therapeutic approaches for improvement of clinical outcome of patients treated with GO.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 6
    Publication Date: 2003-05-01
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 7
    Publication Date: 2006-11-16
    Description: Background: CD33, the target for the anti-AML immunoconjugate, gemtuzumab ozogamicin (GO; Mylotarg™), contains two cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs). We have previously shown that these motifs control uptake of antibody-bound CD33 and GO-induced cytotoxicity. In this study, we determined which phosphorylation state favors uptake of antibody-bound CD33, identified proteins that bind to CD33 in an ITIM-dependent manner, and assessed their importance for CD33 internalization by siRNA-based gene silencing. Methods: Internalization of anti-CD33 antibodies was measured by flow cytometry in the presence or absence of the tyrosine phosphatase inhibitor, pervanadate, in human CD33+ AML cell lines (ML-1, HL-60, NB4, U937, TF-1) and CD33− Jurkat T cells infected with wild-type and mutant CD33. Pull-down experiments were performed with glutathione S-transferase (GST) proteins fused to phosphorylated cytoplasmic tails of CD33, using human myeloid cell lysates. Co-immunoprecipitations were performed with myeloid cell lines expressing HA-tagged wild-type CD33. Lentivirus-based siRNA constructs were generated for gene silencing, and expressed in human CD33+ AML cell lines. Results: Pervanadate significantly increased uptake of anti-CD33 antibodies in human AML cell lines; this effect was dependent upon the integrity of the ITIMs and was prevented by co-treatment with the Src tyrosine kinase inhibitor PP2, suggesting that Src family kinase-dependent phosphorylation of the ITIMs critically controls uptake of antibody-bound CD33, possibly by altering which proteins binds to CD33 or by facilitating binding of adaptor-proteins required for endocytosis. We identified several proteins, including the tyrosine phophatases, SHP-1 and SHP-2, and the non-receptor tyrosine kinase, Syk, which bound to phosphorylated wild-type and mutant CD33 in a manner that paralleled the endocytic properties of the corresponding CD33 protein. Since these three proteins have been implicated in endocytic processes of other cell surface proteins, we assessed their role in uptake of antibody-bound CD33 by siRNA-mediated gene silencing. Simultaneous depletion of SHP-1 and SHP-2, but not SHP-1 or SHP-2 alone, significantly increased internalization of antibody-bound CD33 in the two AML cell lines with the highest cell surface expression of CD33, whereas no effect was seen in two other cell lines with lower CD33 expression levels. In contrast, depletion of Syk, whose expression has previously been correlated to the inhibitory effect of anti-CD33 antibodies on AML cell growth, failed to affect antibody internalization in the cell lines assessed. Conclusion: These studies indicate that the phosphorylation status of the ITIMs controls uptake of antibody-bound CD33. In line with this model, SHP-1 and SHP-2, which have been shown to dephosphorylate CD33 in vitro, can affect this endocytic process. Thus, our data imply manipulation of the phosphorylation state of CD33, e.g. by activating Src family kinases or interfering with phosphatases as a novel means to increase uptake of anti-CD33 antibody-based therapeutics such as GO. Finally, the variable effect of SHP-1 and SHP-2 depletion suggests that there are significant cell-type specific differences in the response to anti-CD33 antibody ligation, for example differences in tyrosine phosphorylation levels and/or activation/recruitment or redundancies of tyrosine phosphatases.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 8
    Publication Date: 2006-11-01
    Description: Background: The anti-acute myeloid leukemia (AML) immunoconjugate, gemtuzumab ozogamicin (GO; Mylotarg™), contains a humanized anti-CD33 antibody (hP67.6) to facilitate uptake of the toxic calicheamicin-γ1 derivative in CD33-positive AML cells. This putative mechanism implies a critical role for the intracellular accumulation of the toxic moiety for GO-induced cytotoxicity. Indeed, drug efflux by P-glycoprotein (Pgp) mediates resistance to GO and correlates with clinical outcome after GO monotherapy. Furthermore, recent in vitro data obtained in human myeloid cell lines have unequivocally demonstrated a quantitative relationship between CD33 expression and GO-induced cytotoxicity. In light of these findings, we have now re-examined the significance of CD33 expression levels on AML blasts and relationship with Pgp activity for clinical outcome of patients treated with GO monotherapy. Methods: Pre-treatment bone marrow samples from patients enrolled in multicenter phase II protocols evaluating the safety and efficacy of GO monotherapy (generally 2 doses of 9 mg/m2 14 days apart) were used for analysis. Relative CD33 expression was quantified by flowcytometry immunophenotyping using the hP67.6 antibody, and linear fluorescence values used for calculations. Pgp function was cytofluorometrically determined by efflux of the fluorescent dye, DiOC2. Results are presented as mean values and 95% confidence intervals. Unpaired t-tests, Pearson correlations, and logistic regression models were used for statistical analysis. Results: Patients achieving a complete remission (CR) or CR with incomplete recovery of platelet counts (CRp) had statistically significantly higher mean CD33 expression levels (71.20 [57.20–85.19], n=69) compared to non-responders (54.44 [48.38–60.51], n=203; p=0.01). There was an inverse relationship between CD33 expression and Pgp efflux (r=−0.23) and this contributed to responders having a statistically significantly lower mean Pgp efflux (1.40 [1.28–1.52], n=57) compared to non-responders (1.83 [1.72–1.95], n=173; p
    Print ISSN: 0006-4971
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  • 9
    Publication Date: 2004-06-01
    Description: The antibody-targeted therapeutic, gemtuzumab ozogamicin (GO, Mylotarg), is approved for treatment of relapsed acute myeloid leukemia (AML). We previously showed that AML blasts from GO refractory patients frequently express the drug transporters P-glycoprotein (Pgp) and/or multidrug resistance protein (MRP). We also previously reported that inhibition of drug transport by the Pgp modulator, cyclosporine A (CSA), can increase GO sensitivity in Pgp+ AML cells and that the peripheral benzodiazepine receptor ligand, PK11195, sensitizes AML cells to standard chemotherapeutics both by inhibiting Pgp-mediated efflux and by promoting mitochondrial apoptosis. We now show that PK11195 also can overcome multiple resistance mechanisms to increase GO sensitivity in AML cells, including resistance associated with expression of drug transporters and/or antiapoptotic proteins. PK11195 substantially increases GO cytotoxicity in AML cells from many different cell lines and primary patient samples, often more effectively than CSA. We also show that PK11195 is nontoxic in NOD/SCID mice and can sensitize xenografted human AML cells to GO. Since PK11195 is well tolerated in humans as a single agent, its further study as a multifunctional chemosensitizer for anti-AML therapies, including GO-based therapies, is warranted. (Blood. 2004;103:4276-4284)
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  • 10
    Publication Date: 2005-11-15
    Description: The peripheral benzodiazepine receptor (pBR) ligand, PK11195, promotes mitochondrial apoptosis and blocks P-glycoprotein (Pgp)-mediated drug efflux to chemosensitize cancer cells at least as well or better than the Pgp modulator, cyclosporine A (CSA). We now show that PK11195 broadly inhibits adenosine triphosphate (ATP)-binding cassette (ABC) transporters in hematologic cancer cell lines and primary leukemia-cell samples, including multidrug resistance protein (MRP), breast cancer resistance protein (BCRP), and/or Pgp. Ectopic expression models confirmed that pBR can directly mediate chemosensitizing by PK11195, presumably via mitochondrial activities, but showed that pBR expression is unnecessary to PK11195-mediated efflux inhibition. PK11195 binds plasma-membrane sites in Pgp-expressing cells, stimulates Pgp-associated adenosine triphosphatase (ATPase) activity, and causes conformational changes in Pgp, suggesting that PK11195 modulates Pgp-mediated efflux by direct transporter interaction(s). PK11195 and CSA bind noncompetitively in Pgp-expressing cells, indicating that PK11195 interacts with Pgp at sites that are distinct from CSA-binding sites. Importantly, PK11195 concentrations that were effective in these in vitro assays can be safely achieved in patients. Because PK11195 promotes chemotherapy-induced apoptosis by a pBR-dependent mitochondrial mechanism and broadly blocks drug efflux by an apparently pBR-independent, ABC transporter-dependent mechanism, PK11195 may be a useful clinical chemosensitizer in cancer patients.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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