Biomaterial Database

Circumvention of P-glycoprotein-mediated drug resistance in human leukaemic cells by non-immunosuppressive cyclosporin D analogue, SDZ PSC 833. 1995

X R Jiang, and S M Kelsey, and Y L Wu, and A C Newland

Department of Haematology, London Hospital Medical College.

Cyclosporin A (CSA) exhibits greater multidrug resistance (MDR) modulating activity in vitro than other MDR modulators such as verapamil and quinidine. However, the immunosuppressive and nephrotoxic effects of CSA may limit its clinical use. PSC 833, a new cyclosporin D derivative, exerts a higher MDR reversal activity but lacks toxic or immunosuppressive effects. The drug-resistant sublines K/DAU100, K/DAU200, K/DAU300, K/DAU400, K/DAU500 and K/DAU600 have been derived from the drug-sensitive parental cell line, K562 cl.6 and CEM/VLB100 is a drug-resistant derivative of CCRF-CEM. We report a comparison of the effects of PSC 833 and CSA on daunorubicin (DAU) transport kinetics and chemosensitivity in these cell lines. Both CEM/VBL100 and K562 cl.6 DAU-resistant cells displayed high levels of P-glycoprotein (PGP), decreased DAU accumulation and increased DAU efflux when compared to their parental cells. PSC 833 was 1.6-, 3.4-, 4.9- and 4.6-fold more effective than CSA in reversing DAU resistance in higher resistance CEM/VLB100, K/DAU400, K/DAU500 and K/DAU600 cells respectively. DAU transport kinetics showed that PSC 833 was more effective than CSA in increasing cellular DAU accumulation and decreasing DAU efflux in higher resistant leukaemia subclones. PSC 833 could restore DAU retention at lower doses and was more active than CSA in all the resistant cells. A 89-100% restoration of intracellular DAU retention were gained by PSC 833 at 1.0 microM in K562 cl.6 DAU-resistant sublines, whereas a 73-100% restoration of DAU retention was obtained by CSA only at 30.0 microM in the same resistant sublines. PSC 833 at 3.0 microM is sufficient to restore full DAU retention in all resistant cells. CSA, however, even at 30.0 microM, cannot confer full restoration of DAU retention in higher resistance K562 cl.6/DAU sublines. By measuring MDR modulator-mediated short-term inhibition of PGP function, PSC 833 was found to be at least 10-30 times more active than CSA. As no effect on DAU retention and sensitivity has been found in sensitive parental cells with PSC 833, it is suggested that PSC 833 may act by blocking the effluxing function of PGP in the resistant leukaemia cells.

UI	MeSH Term	Description	Entries
D002470	Cell Survival	The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability.	Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D003524	Cyclosporins	A group of closely related cyclic undecapeptides from the fungi Trichoderma polysporum and Cylindocarpon lucidum. They have some antineoplastic and antifungal action and significant immunosuppressive effects. Cyclosporins have been proposed as adjuvants in tissue and organ transplantation to suppress graft rejection.	Cyclosporines
D003630	Daunorubicin	A very toxic anthracycline aminoglycoside antineoplastic isolated from Streptomyces peucetius and others, used in treatment of LEUKEMIA and other NEOPLASMS.	Daunomycin,Rubidomycin,Rubomycin,Cerubidine,Dauno-Rubidomycine,Daunoblastin,Daunoblastine,Daunorubicin Hydrochloride,NSC-82151,Dauno Rubidomycine,Hydrochloride, Daunorubicin,NSC 82151,NSC82151
D004915	Leukemia, Erythroblastic, Acute	A myeloproliferative disorder characterized by neoplastic proliferation of erythroblastic and myeloblastic elements with atypical erythroblasts and myeloblasts in the peripheral blood.	Di Guglielmo's Disease,Erythremic Myelosis,Erythroblastic Leukemia, Acute,Erythroleukemia,Leukemia, Myeloid, Acute, M6,Myeloid Leukemia, Acute, M6,Di Guglielmo Disease,Acute Erythroblastic Leukemia,Acute Erythroblastic Leukemias,Di Guglielmos Disease,Disease, Di Guglielmo,Disease, Di Guglielmo's,Erythremic Myeloses,Erythroblastic Leukemias, Acute,Erythroleukemias,Leukemia, Acute Erythroblastic,Leukemias, Acute Erythroblastic,Myeloses, Erythremic,Myelosis, Erythremic
D005455	Fluorescent Antibody Technique	Test for tissue antigen using either a direct method, by conjugation of antibody with fluorescent dye (FLUORESCENT ANTIBODY TECHNIQUE, DIRECT) or an indirect method, by formation of antigen-antibody complex which is then labeled with fluorescein-conjugated anti-immunoglobulin antibody (FLUORESCENT ANTIBODY TECHNIQUE, INDIRECT). The tissue is then examined by fluorescence microscopy.	Antinuclear Antibody Test, Fluorescent,Coon's Technique,Fluorescent Antinuclear Antibody Test,Fluorescent Protein Tracing,Immunofluorescence Technique,Coon's Technic,Fluorescent Antibody Technic,Immunofluorescence,Immunofluorescence Technic,Antibody Technic, Fluorescent,Antibody Technics, Fluorescent,Antibody Technique, Fluorescent,Antibody Techniques, Fluorescent,Coon Technic,Coon Technique,Coons Technic,Coons Technique,Fluorescent Antibody Technics,Fluorescent Antibody Techniques,Fluorescent Protein Tracings,Immunofluorescence Technics,Immunofluorescence Techniques,Protein Tracing, Fluorescent,Protein Tracings, Fluorescent,Technic, Coon's,Technic, Fluorescent Antibody,Technic, Immunofluorescence,Technics, Fluorescent Antibody,Technics, Immunofluorescence,Technique, Coon's,Technique, Fluorescent Antibody,Technique, Immunofluorescence,Techniques, Fluorescent Antibody,Techniques, Immunofluorescence,Tracing, Fluorescent Protein,Tracings, Fluorescent Protein
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D014407	Tumor Cells, Cultured	Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.	Cultured Tumor Cells,Neoplastic Cells, Cultured,Cultured Neoplastic Cells,Cell, Cultured Neoplastic,Cell, Cultured Tumor,Cells, Cultured Neoplastic,Cells, Cultured Tumor,Cultured Neoplastic Cell,Cultured Tumor Cell,Neoplastic Cell, Cultured,Tumor Cell, Cultured
D015458	Leukemia, T-Cell	A malignant disease of the T-LYMPHOCYTES in the bone marrow, thymus, and/or blood.	Leukemia, Lymphocytic, T-Cell,Lymphocytic Leukemia, T-Cell,T-Cell Leukemia,T-Lymphocytic Leukemia,Leukemia, Lymphocytic, T Cell,T Lymphocytic Leukemia,Leukemia, T Cell,Leukemia, T Lymphocytic,Leukemia, T-Cell Lymphocytic,Leukemia, T-Lymphocytic,Leukemias, T Lymphocytic,Leukemias, T-Cell,Leukemias, T-Cell Lymphocytic,Leukemias, T-Lymphocytic,Lymphocytic Leukemia, T,Lymphocytic Leukemia, T Cell,Lymphocytic Leukemias, T,Lymphocytic Leukemias, T-Cell,T Cell Leukemia,T Lymphocytic Leukemias,T-Cell Leukemias,T-Cell Lymphocytic Leukemia,T-Cell Lymphocytic Leukemias,T-Lymphocytic Leukemias
D016572	Cyclosporine	A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. (From Martindale, The Extra Pharmacopoeia, 30th ed).	Cyclosporin A,Ciclosporin,CsA-Neoral,CyA-NOF,Cyclosporin,Cyclosporine A,Neoral,OL 27-400,Sandimmun,Sandimmun Neoral,Sandimmune,CsA Neoral,CsANeoral,CyA NOF,OL 27 400,OL 27400
D018432	Drug Resistance, Multiple	Simultaneous resistance to several structurally and functionally distinct drugs.	Drug Resistance, Extensively,Extensively Drug Resistance,Extensively-Drug Resistance,Multidrug Resistance,Multi-Drug Resistance,Extensively Drug Resistances,Extensively-Drug Resistances,Multiple Drug Resistance,Resistance, Extensively Drug,Resistance, Extensively-Drug,Resistance, Multiple Drug