DRUG-INDUCED DNA MODIFICATION IN BUCCAL CELLS OF CANCER-PATIENTS RECEIVING CARBOPLATIN AND CISPLATIN COMBINATION CHEMOTHERAPY, AS DETERMINED BY AN IMMUNOCYTOCHEMICAL METHOD - INTERINDIVIDUAL VARIATION AND CORRELATION WITH DISEASE RESPONSE

Twenty-six patients with a variety of tumor types were treated accordi ng to a phase 1 experimental treatment protocol consisting of repetiti ve cycles of diammine(1,1-cyclobutanedicarboxylato)platinum(II) (carbo platin, 200-480 mg/m2) at day 1 and cis-diamminedichloroplatinum(II) ( cisplatin, 50-100 mg/m2) at day 3. Buccal cells were collected in one or two treatment cycles prior to carboplatin, 24 h after carboplatin, just prior to cisplatin, and approximately 24 h after cisplatin admini stration. Drug-induced DNA modification was visualized at the single c ell level by antiserum NKI-A59 and quantitated by microdensitometry. A ll (39 of 39) treatments with carboplatin, and almost all (33 of 35) t reatments with cisplatin resulted in an increase in nuclear stain. Int erindividual variation in drug-induced, adduct-specific nuclear stain amounted to a factor of 5-8 for carboplatin and 5-12 for cisplatin. Th is drug-induced increase was, however, not related to the dose of eith er carboplatin or cisplatin, suggesting that large interindividual dif ferences in DNA adduct formation and/or repair obscured the effects of dose variation within the relatively small range used for the drugs ( 2.4 for carboplatin and 2.0 for cisplatin). This explanation was stren gthened by the good reproducibility of the immunocytochemical assay an d by the reasonable correlation between carboplatin-induced nuclear st ain in cycles 1 and 2 (correlation coefficient, 0.69; P = 0.009). Mean carboplatin-induced nuclear stain was significantly higher in the fir st cycle than in the second cycle (P = 0.0001) but this difference was no longer significant when drug-induced nuclear stain was corrected f or carboplatin dose. Differences in cisplatin-induced nuclear stain be tween cycle 1 and cycle 2 were small and not significant. Carboplatin- induced nuclear stain was significantly higher in the partial responde rs than in the nonresponders (P < 0.0001, two cycles combined); the le vel of statistical significance remained the same after dose correctio n. Cisplatin-induced nuclear stain did not differ significantly betwee n partial responders and nonresponders; this result might, however, be confounded to some extent by remaining carboplatin-induced nuclear st ain at the moment of cisplatin administration. It is concluded that de termination of the extent of platinum-induced DNA modification might b e helpful in predicting the tumor response in cancer patients.