CROSS-RESISTANCE AND COLLATERAL SENSITIVITY TO NATURAL PRODUCT DRUGS IN CISPLATIN-SENSITIVE AND RESISTANT RAT LYMPHOMA AND HUMAN OVARIAN-CARCINOMA CELLS

The cytotoxicity of mitotic spindle poisons, vinca alkaloids and the a nthracycline, adriamycin, against cisplatin-sensitive and -resistant r at lymphoma and human ovarian carcinoma cell lines was investigated. I nterestingly, it was found that all cell lines were more sensitive to the mitotic spindle poisons, vincristine and vinblastine. Adriamycin w as the least effective and taxol had intermediate activity. The Walker rat lymphoma cell line resistant to cisplatin (WR) exhibited the mult iple drug resistance phenotype since it showed collateral resistance t o all drugs (ranging from twofold to taxol, colcemid and colchicine an d sixfold to the vinca alkaloids). Verapamil potentiated the cytotoxic activity of adriamycin and vincristine in a striking fashion with the Walker cells. P-glycoprotein was found to be present in the plasma me mbranes of the Walker cells with approximately a 2.5-fold increase in the WR as compared to the sensitive (WS) cells. Glutathione levels wer e elevated in all of the cisplatin-resistant cell lines when compared to the cisplatin-sensitive parental cell lines. A profound effect of b uthionine sulfoximine pretreatment on adriamycin cytotoxicity was obse rved. Glutathione S-transferase (pi) was present in all the human cell lines but the WS cells had markedly lower levels (almost negligible) when compared to the WR cells. These observations imply that cisplatin -resistant cells may be more sensitive to mitotic spindle poisons and vinca alkaloids, irrespective of the mechanism of platinum resistance, and that the cytotoxicity of vinca alkaloids could be further modulat ed by verapamil, irrespective of the presence or absence of P-glycopro tein.