O-6-methylguanine formation, repair protein depletion and clinical outcomewith a 4 hr schedule of temozolomide in the treatment of advanced melanoma: Results of phase II study

O-6-Methylguanine-DNA methyltransferase (MGMT) is a major determinant of re sistance to temozolomide. Its levels are depleted in lymphocytes after drug administration, but there is partial recovery by 24 hr, the usual time of subsequent dosing. Administering subsequent doses of temozolomide at the MG MT nadir could enhance its effectiveness, by increasing the amount of O-6-m ethylguanine (O-6-meG) in DNA. We evaluated the efficacy of such a schedule of temozolomide and determined the kinetics of MGMT depletion and O-6-meG formation in DNA following treatment. Thirty patients with advanced maligna nt melanoma were treated with temozolomide 1,000 mg/m(2) equally split into 5 doses over a 16 hr period every 28 days. O-6-meG formation was determine d in peripheral blood mononuclear cell (PBMC) DNA and, in a subset of patie nts, in tumor tissue during the first treatment cycle. MGMT levels fell rap idly with dosing, reaching a nadir in PBMCs of 18.0 +/- 2.26% of initial le vels. O-6-meG levels increased during the treatment period, peaking at 11.1 +/- 1.25 mu mol/mol dG in PBMCs and at 4.25 +/- 0.79 mu mol/mol dG in tumo r biopsies. The main toxicities were grade IV thrombocytopenia in 12 patien ts (42.8%) and grade IV neutropenia in 11 patients(39.2%), associated with fever in 8 cases. There were 7 responses (I complete), for an overall respo nse rate of 23.3%; median overall survival was 6.1 months. The compressed s chedule has activity against melanoma, with greater MGMT depletion and O-6- meG formation than previously reported for O-6-alkylating agent regimens. M yelosuppression precludes its wider application, but MGMT in PBMCs predicte d the dose intensity of temozolomide that patients could sustain, suggestin g a means by which individuals suitable for this approach might be identifi ed. Int. J, Cancer 88:469-473, 2000. (C) 2000 Wiley-Liss. Inc.