Purpose: O-6-Benzylguanine is a potent inactivator of the DNA-repair protein, O-6-alkylguanine-DNA alkyl-transferase (AGT), that enhances sensitivity to nitrosoureas in tumor-cell lines and tumor-bearing animals. The objective of this study wets to determine the pharmacokinetics and metabolic fate of O-6-Benzylguanine in humans and ifs effect on AGT activity in peripheral-blood mononuclear cells (PBMCs). Patients and Methods: Twenty-five cancer patients were treated with O-6-Benzylguanine at a dose level of 10, 20, 40, and 80 mg/m(2) intravenously (IV) over 1 hour. Plasma and urine samples were collected and analyzed for O-6-Benzylguanine and O-6-Benzyl-8-oxoguanine concentrations, AOT activity in PBMCs was determined up to 2 weeks postinfusion. Results: There was no toxicity attributable to O-6- Benzylguanine alone at all doses tested. O-6-Benzylguanine rapidly disappeared from plasma and was converted to a major metabolite, O-6-Benzyl-8-oxoguanine. The half-life of O-6-Benzyl-8-oxoguanine increased with dose from 2.8 to 9.2 hours at doses of 10 and 80 mg/m(2), respectively, The maximum concentration C-max and area under the concentration-time curve (AUC) for O-6-Benzyl-8-oxoguanine were, respectively, 2.2- and 12-to 29-fold greater than those of O-6-Benzylguanine. At all doses, depletion of AGT activity was observed in lymphocytes with a return to baseline by 1 week posttreatment. Conclusion: This study demonstrates that administration of O-6-Benzylguanine to humans results in a rapid conversion to O-6-Benzyl-8-oxoguanine, which follows nonlinear kinetics, Both compounds contribute to on effective depletion of AGT activity in lymphocytes; however, prolonged depletion of AGT activity is likely due primarily to the effect of O-6-Benzyl-8-oxoguanine. (C) 1998 by American Society of Clinical Oncology.
