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  • 1
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    German Medical Science; Düsseldorf, Köln
    In:  27. Deutscher Krebskongress; 20060322-20060326; Berlin; DOCPO118 /20060320/
    Publication Date: 2006-04-21
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 2
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; TUMOR-CELLS ; PATHWAYS ; DRUG ; COMPONENTS ; LINES ; IMPACT ; mechanisms ; DOWN-REGULATION ; BONE-MARROW ; RECOGNITION ; leukemia ; MHC CLASS-I ; NATURAL-KILLER-CELLS ; NK cells ; allogeneic ; BONE-MARROW-TRANSPLANTATION ; CROSS-RESISTANCE ; CYTOCHROME-C RELEASE ; CYTOSOLIC DELIVERY ; CYTOTOXIC EFFECTOR-CELLS ; graft-versus-leukemia ; GRANZYME-B ; HLA class I ; INITIATES APOPTOSIS ; PERFORIN ; TARGET-CELLS
    Abstract: Background and Objectives. Drug-resistant leukemia cells may exhibit cross-resistance towards immunological, effector mechanisms by alterations of apoptosis pathways. This is particularly relevant in allogeneic bone m, arrow transplantation for leukemia, where the graft-versus-leukemia effect acts on cells pretreated with cytostatic drugs. Here, we clarify the mechanism underlying cross-resistance of drug- resistant variants of the T-leukemia cell, line CEM towards natural killer cells. Design and Methods. We determined the sensitivity of. different CEM sublines to natural killer (NK) cytotoxicity, and separately analyzed the components of the killing machinery by detection of granzyme B-induced caspase, cleavage and HLA class I-dependent recognition mechanisms. Furthermore, We studied regulation of HLA class I expression comparing CEM with other cell lines. Results. We found that CEM cells resistant to cytostatic drugs or CD95 were cross- resistant towards NK cells from a variety of donors. Granzyme B-induced caspase and PARP cleavage in the sensitive and resistant cells were comparable, indicating that downstream apoptosis pathways were not altered in the drug-resistant cells, HLA class I molecules were upregulation in the resistant cells, inhibiting NK cells at the level of killer/target recognition. HLA class I upregulation was not found in other leukemia cell lines. Interpretation and Conclusions., This is the first description of HLA class I-mediated, NK cross- resistance, in drug-resistant cells. This finding may have a,clinical impact since it may be considered as a possible reason for resistance to a graft-versus-leukemia approach in allogeneic bone marrow transplantation
    Type of Publication: Journal article published
    PubMed ID: 12745270
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  • 3
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; IN-VIVO ; THERAPY ; SYSTEM ; DEATH ; MONOCLONAL-ANTIBODY ; TUMORS ; LINES ; ACTIVATION ; LIGAND ; MECHANISM ; INDUCTION ; mechanisms ; CELL-LINES ; DOWN-REGULATION ; resistance ; CD95 ligand ; CELL-DEATH ; INDUCED APOPTOSIS ; CELL-LINE ; chemotherapy ; leukemia ; LINE ; poly(ADP-ribose) polymerase ; doxorubicin ; sensitivity ; drug resistance ; cell lines ; protease ; MOLECULAR-CLONING ; EFFLUX ; CD95 ; neuroblastoma ; METHOTREXATE ; SURFACE ANTIGEN ; LEUKEMIA-CELLS ; HUMAN T-CELLS ; SOLID TUMORS ; ROLES ; LIGAND EXPRESSION ; FAS ANTIGEN ; CANCER-CHEMOTHERAPY ; LEUKEMIAS ; ICE/CED-3 PROTEASE
    Abstract: 0470,english,The molecular mechanisms for sensitivity and resistance of tumor cells towards chemotherapy are only partially understood, In chemosensitive leukemias and solid tumors, anticancer drugs have been shown to induce apoptosis. We previously identified activation of the CD95 (APO-1/Fas) receptor/CD95 ligand (CD95/CD95-L) system as a key mechanism for drug-induced apoptosis. Here, we show that therapeutic concentrations of doxorubicin, methotrexate and cytarabine also induce apoptosis via activation of the CD95 system in primary leukemia cells in vivo, CD95-resistant and doxorubicin-resistant leukemia and neuroblastoma cells display cross-resistance for induction of cell death. Down-regulation of CD95 expression was found in drug- resistant and CD95-resistant cell lines. Furthermore, up- regulation of CD95-L, previously shown to mediate drug-induced apoptosis in a variety of tumor cells, was completely blocked in doxorubicin-resistant cells. The prototype caspase (ICE/Ced-3 protease) substrate, poly(ADP-ribose)polymerase (PARP), was cleaved in sensitive, but not in resistant tumor cells following CD95 triggering or drug treatment. Since failure to activate CD95- L was not due to decreased drug uptake or increased drug efflux, non-multi-drug resistance (non-MDR) mechanisms are involved in this type of resistance. These findings suggested that an intact CD95 system plays a key role in determining sensitivity or resistance towards anticancer therapy
    Type of Publication: Journal article published
    PubMed ID: 9369415
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  • 4
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    German Medical Science; Düsseldorf, Köln
    In:  27. Deutscher Krebskongress; 20060322-20060326; Berlin; DOCPO381 /20060320/
    Publication Date: 2006-04-21
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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