In two human ovarian tumor cell lines, resistance to cis-diamminedichloroplatinum(II) (CDDP) was induced by continuous exposure of the parental lines to an increasing CDDP concentration in the culture medium. In contrast, a six times repeated pulse exposure of 6.7 µm or 16.7 µm CDDP for 1 h did not result in a cell line that showed a higher survival in CDDP-containing medium. The ID50 value for CDDP was seven to eight times higher for the resistant lines and those lines were able to grow at 3.3 µm CDDP. The induced resistance was stable during at least 25 doubling times. The CDDP-resistant sublines showed cross-resistance to the CDDP-analogues cis-diammine-1,1-cyclobutane-dicarboxylateplatinum(II) and cis-dichlorobis(isopropylamine)-trans-dihydroxyplatinum(IV) indicating that resistance to the different platinum compounds is generated by a common mechanism. The resistant sublines were also cross-resistant to mitomycin C and melphalan. The degree of cross-resistance for the tested drugs varied widely between the two cell lines. Resistance to CDDP was clearly correlated to decreased amounts of platinum in the resistant cells as compared to the sensitive cells. The amplification and expression of genes encoding proteins that had been shown to be involved in multidrug resistance, e.g., the Mr 170,000 P-glycoprotein was also studied. No amplification or overexpression of these genes could be shown in the resistant cell lines.
This work was supported by a grant from the Koningin Wilhemina Fonds (Netherlands Cancer Foundation).