ACCUMULATION OF O6-METHYLGUANINE IN HUMAN DNA AFTER THERAPEUTIC EXPOSURE TO METHYLATING AGENTS AND ITS RELATIONSHIP WITH BIOLOGICAL EFFECTS

O6-Methylguanine has been measured in peripheral blood leukocytes of 1 4 patients during one or more cycles of treatment with procarbazine (d aily treatment for 10 days) and in 12 patients during one or more cycl es of treatment with dacarbazine (single dose per cycle). Adduct forma tion at levels up to about 0.4 fmole/mug DNA was detected in all proca rbazine- and all but one dacarbazine-treated patients at some point af ter treatment. O6-Methylguanine accumulated during procarbazine treatm ent in a dose-related manner (mean rate of accumulation 2.8 x 10(-4) f mole/mug DNA per mg/m2 dose) and appeared to approach a plateau by the end of the cycle (above 600 mg/m2 cumulative dose). The average rate of O6-methylguanine formation 2 hr after dacarbazine treatment was 11 +/- 8 X 10(-4) fmole/mug DNA per mg/m2 dose. Individuals examined on m ore than one treatment cycle with either drug showed broadly similar m ethylation responses. The rate of adduct accumulation showed a nonsign ificant, negative correlation with the pretreatment lymphocyte levels of the repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT) in the case of procarbazine and no correlation in the case of dacarbazine. N o consistent lymphocyte AGT depletion was noted as a result of treatme nt with either drug. No correlation between O6-methylguanine formation and hematological toxicity was observed. In eight patients showing fu ll remission after treatment with dacarbazine, the value of O6-methylg uanine (averaged over all the cycles) was 0.252 +/- 0.120 fmole/mug DN A while in four patients showing partial or no response it was 0.087 /- 0.110 fmole/mug DNA (p < 0.05). One of the two nonresponding procar bazine-treated patients showed very low levels of O6-methylguanine dur ing a cycle of observation of DNA adduct formation. Human blood leukoc ytes are about 5-fold less susceptible than those of the rat to accumu lation of O6-methylguanine during exposure to procarbazine. Furthermor e, similar adduct levels were found in rat peripheral blood leukocytes and lymphocytes, bone marrow, and lymph nodes, suggesting that levels observed in human blood leukocytes may reflect those in the presumed target tissues for the leukemogenic (bone marrow) and the therapeutic (lymph nodes) effects of procarbazine. The possible use of these obser vations in the assessment orcarcinogenic risks to humans exposed to pr ocarbazine or environmental methylating agents such as dimethylnitrosa mine is discussed.