Establishment and Characterization of Acquired Resistance to Platinum Anticancer Drugs in Human Ovarian Carcinoma Cells

To investigate differences in resistance to cis -diamminedichloroplatinum(II) (CDDP) and diammine (1,1-cyclobutanecarboxylato)platinum(II) (CBDCA), and their newly developed derivative, ((—)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutanedicarboxylato)platinum (II)) (DWA2114R), four types of resistant cell lines were established from a parental cell line (NOS2) of a serous cystadeno-carcinoma of the ovary. The cross-resistance of CDDP-resistant cells (NOS2CR1 and NOS2CR2) to DWA2114R was slight (only 25% of the resistance to CDDP), and no cross-resistance was observed to anticancer drugs other than the CDDP derivative, except to camptothecin (CPT-11) in the case of NOS2CR2 cells. The cross-resistance of CBDCA-resistant cells (NOS2CBR) to DWA2114R was slight (only about 1/3 of the resistance to CBDCA), and no cross-resistance was observed among anticancer drugs other than the CDDP derivative. On the other hand, DWA2114R-resistant cells (NOS2DR) showed a high cross-resistance to CDDP, CBDCA, etoposide (VP-16), and CPT-11. Intracellular accumulations of CDDP and CBDCA were markedly reduced in NOS2CR1, NOS2CR2, and NOS2CBR cells compared to those in NOS2 cells, but were reduced only slightly in NOS2DR cells. Intracellular accumulation of DWA2114R was reduced somewhat in the four types of resistant cells. Glutathione S-transferase activity was not increased in any of the four types of resistant cells, and intracellular GSH concentration was increased only in NOS2CR2 cells (by 2.6 fold). From these results, we consider that the resistance mechanisms against CDDP and CDBCA are similar, and reduction of intracellular drug accumulations is a significant factor. Resistance to DWA2114R differed from resistance to CDDP and CBDCA in both cross-resistance spectrum and resistance mechanism, indicating that reduction in intracellular drug accumulation is not the major resistance mechanism.