In vivo formation and repair of O6-methylguanine in human leukocyte DNA after intravenous exposure to dacarbazine.

Blood leukocyte DNA obtained from 11 Hodgkin's disease patients undergoing ABVD chemotherapy was analysed for the presence of the precarcinogenic adduct O6-methylguanine (O6-meG) at various times (1-2 h up to 49 h) after i.v. treatment with the methylating drug dacarbazine. Adduct formation was detected in all but one of the patients examined at levels ranging up to 0.45 fmol/micrograms DNA (7.2 x 10(-7) mol/mol guanine). The levels of the adduct decreased by approximately 30% over the 24 h following exposure and were usually not detectable 49 h after exposure. In five out of seven individuals examined after more than one treatment, consistent methylation responses were noted, while in the remaining two cases the responses were mixed. No correlation between the extent of adduct formation and lymphocyte levels of the repair enzyme O6-alkylguanine-DNA alkyltransferase was observed. The average extent of O6-meG formation 1 h after dacarbazine treatment was (4.3 +/- 3.1) x 10(-2) fmol/micrograms DNA per mg/kg dose [( 1.2 +/- 0.8) x 10(-3) fmol/micrograms DNA per mg/m2 dose)]. Following exposure of rats to similar doses of dacarbazine, the corresponding levels of adduct in blood leukocyte DNA were 1.1 x 10(-2) fmol/micrograms DNA per mg/kg dose (2.6 x 10(-3) fmol/micrograms DNA per mg/m2 dose).