Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma

Purpose: The major mechanism of resistance to alkylnitrosourea therapy is the DNA repair protein O-6-alkylguanine-DNA alkyltransferase (AGT), which removes chlorethylation or methylation damage from the O-6-position of guanine. O-6-benzylguanine (O-6-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial to define the presurgical dose required for depletion of tumor AGT activity in patients with malignant glioma. Material and Methods: patients were to be treated 18 hours before craniotomy with intravenous doses that ranged between 40 and 100 mg/m(2) given over 1 hour. Resected tumor was snap-frozen in liquid nitrogen and AGT activity analyzed by high-pressure liquid chromatography (HPLC). Up to 13 patients were treated at a specific dose of O-6-BG, with a target end point of greater than or equal to 11 of 13 patients with undetectable tumor AGT levels (< 10 fmol/mg protein). Results: Thirty patients with malignant gliomas were enrolled; with 11 of 11 patients treated at 100 mg/m(2) O-6-BG demonstrating tumor AGT levels less than 10 fmol/mg protein. No toxicity was noted in any patient treated. Conclusion: These results indicate that 100 mg/m(2) of O-6-BG can maintain tumor AGT levels less than 10 fmol/mg protein for at least 18 hours after treatment, a time interval in which bis(2-chloroethyl)nitrosourea (BCNU)-induced chloroethyl adducts are fully converted into interstrand cross-links. A 100-mg/m(2) dose of O-6-BG will be used in combination with BCNU in another phase I trial designed to determine the maximal-tolerated dose of BCNU. (C) 1998 by American Society of Clinical Oncology.