Induction of multiple‐drug resistance during anti‐neoplastic chemotherapy in vitro

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Abstract
Induction of P‐glycoprotein‐related multi‐drug‐resistance (MDR) has been shown innormal and malignant tissues to result from environmental stresses such as heat shock, exposure to carcinogens or X‐ray irradiation. To identify conditions under which MDR is enhanced during anti‐neoplastic chemotherapy, a cell line showing low‐level intrinsic MDR was investigated. In the pleural mesothelioma cell line, PXF1118, < 1% of cells ex‐ pressed P‐glycoprotein (P‐gp), as shown by immunocytochemical staining with monoclonal antibody (MAb) MRK16. Exposure of PXF1118 to vincristine, vindesine, vinblastine or doxorubicin for 2‐3 weeks led to an increase in the MDR cell fraction of up to 15‐28% during 2 to 3 weeks. For doxorubicin and vindesine, dose‐dependence was observed: drug concentrations not capable of eliciting cytotoxicity failed to induce significant P‐gp expression. Nutrient starvation in aging medium, exposure to activated cyclophosphamide (even at high concentrations) or cisplatin caused only negligible MDR induction. After exposure to vindesine for 6 weeks, tumor colonies exhibited highly enhanced resistance to Vinca alkaloids, doxorubicin, etoposide and dacarbacine, whereas their sensitivity to mitomycin, activated cyclophos hamide or cisplatin remained unchanged. As determined by [3H]‐thymidine uptake and proliferation antigen expression, induction of MDR phenotype was observed at minimal proliferative activity with no change in cell count during exposure to anti‐cancer drugs, thus suggesting that the drug treatments changed the phenotype of the cells rather than selecting for a resistant sub‐population. In addition, changes in cell differentiation were observed during MDR induction. Induction of P‐gp during exposure to anti‐cancer drugs thus provides a model for MDR development during initially successful chemotherapy.