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  • Title: Modulation of adriamycin cytotoxicity and transport in drug-sensitive and multidrug-resistant Chinese hamster ovary cells by hyperthermia and cyclosporin A.
    Author: Larrivée B, Averill DA.
    Journal: Cancer Chemother Pharmacol; 2000; 45(3):219-30. PubMed ID: 10663640.
    Abstract:
    PURPOSE: Chemosensitizers such as cyclosporin A can increase intracellular accumulation of chemotherapeutic agents such as Adriamycin in certain multidrug-resistant (MDR) cell lines with overexpression of P-glycoprotein. It is likely that, when combined with cyclosporin A, hyperthermia could increase membrane permeability to Adriamycin and enhance its cytotoxic effects. The ability of both hyperthermia and cyclosporin A to modulate the cytotoxicity, transport and subcellular distribution pattern of Adriamycin was studied in a pleiotropic MDR Chinese hamster ovary cell line (CH(R)C5) and in the drug-sensitive parent line (AuxB1). METHODS: Adriamycin cytotoxicity was evaluated by clonogenic cell survival, drug transport using [(14)C]-labeled Adriamycin and intracellular drug distribution by fluorescence microscopy. RESULTS: Adriamycin cytotoxicity was increased in both drug-sensitive and MDR cells by cyclosporin A (5 microM) alone, and by hyperthermia alone (41-43 degrees C) only in sensitive cells. However, when cyclosporin A and 42 degrees C hyperthermia were used in combination, a large increase in drug cytotoxicity occurred in both cell lines. This effect increased with time and was temperature-dependent. The increase in Adriamycin cytotoxicity caused by cyclosporin A and hyperthermia was accompanied by alterations in membrane permeability to the drug. Cyclosporin A increased [(14)C]Adriamycin uptake, while drug efflux decreased, for both AuxB1 and CH(R)C5 cells and nuclei. For AuxB1 cells only, drug distribution studies showed that cyclosporin A promoted an increase in both nuclear and cytoplasmic drug accumulation. Hyperthermia, combined with cyclosporin A, increased [(14)C]Adriamycin uptake. This effect was seen as an increase in intensity of nuclear and cytosolic drug fluorescence in both cell lines. Cyclosporin A alone diminished drug efflux and caused Adriamycin to remain firmly bound in the nucleus of AuxB1 cells, while it remained primarily in the cytoplasm of CH(R)C5 cells. CONCLUSIONS: Hyperthermia alone had little effect on Adriamycin cytotoxicity and transport in MDR cells, in contrast to drug-sensitive cells. This suggests that P-glycoprotein is fully functional in these MDR cells. Our findings suggest that cyclosporin A and hyperthermia could be beneficial by increasing intracellular drug accumulation, thus improving the effectiveness of Adriamycin against both drug-sensitive and MDR cells within a localized target region.
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