Platinum-DNA adducts in leukocyte DNA correlate with disease response in ovarian cancer patients receiving platinum-based chemotherapy

Abstract

Fifty-five ovarian cancer patients receiving platinum drug-based chemotherapy have been studied prospectively to determine the extent of formation of the bidentate intrastrand adducts of diammineplatinum covalently attached to the N7 positions of adenosine and/or guanosine in leukocyte DNA. Data for clinical response, obtained from medical records, were then correlated with the adduct values. Patients were treated with platinum-based single-agent or combination chemotherapy containing cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum on approved experimental protocols. Adduct measurements were performed by ELISA, and disease response to therapy was assessed by standard oncologic criteria. This study comprises a total of 101 blood samples obtained after intravenous cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum infusion from 55 individuals, and in each case the highest (or "peak") adduct level for each patient was chosen for statistical analysis. Values for median adduct levels in patients grouped by complete response, partial response, and no response were 212, 193, and 62 amol of adduct per microgram of DNA, respectively. Analysis of these data by Jonckheere's test (an extension of the Mann-Whitney test) shows that higher levels of adduct formation correlates with disease response with a two-sided P value of 0.030. Of eight patients on single-agent therapy whose buffy-coat samples did not have measurable adduct levels, none responded to therapy. Analysis of these data using the exact test for trend shows that the formation of adduct at a level of 160 amol/micrograms of DNA or greater correlates with disease response with a two-sided P value of 0.032. Thus in ovarian cancer patients, the formation of the intrastrand diammineplatinum adducts in leukocyte DNA is associated with favorable disease response to cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum chemotherapy.