Correlation of the response to cisplatin of human ovarian cancer cell lines, originating from one tumor but with different sensitivity, with the recovery of DNA adducts.

Abstract

Cis-Diamminedichloroplatinum(II) (CDDP) is used in the treatment of various cancers, with or without ionizing radiation. During treatment, resistance may develop, and cross-resistance can also occur. DNA is the main target for CDDP and ionizing radiation, and we therefore evaluated the correlation between the amount of CDDP-DNA adducts and the cytotoxic activity of CDDP in human ovarian cancer cell lines with different platinum sensitivities. DNA-adduct levels were investigated 18 hr after CDDP exposure in three cell lines originating from the same human ovarian cancer. The least sensitive cells appeared to have the largest amounts of CDDP-DNA adducts, while the most sensitive had higher adduct levels than the parental cells. The proportion of the four adducts measured (i.e., Pt-G, Pt-AG, Pt-GG, and G-Pt-G) was comparable in all cell lines, with a preference for Pt-GG adduct formation (> 50% of the adducts). Intracellular CDDP concentrations were higher in sensitive than in resistant cells, in contrast to the degree of CDDP adduct formation. Data obtained following continuous exposure of CDDP-resistant cells to CDDP suggest that DNA repair is partly responsible for resistance to CDDP. We conclude that the amount of CDDP-DNA adduct formation in cancer cells is not a predictor of CDDP cytotoxicity.