Papers Published

1. HS Friedman, DM Kokkinakis, J Pluda, AH Friedman, I Cokgor, MM Haglund, DM Ashley, J Rich, ME Dolan, AE Pegg, RC Moschel, RE McLendon, T Kerby, JE Herndon, DD Bigner, SC Schold, Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma., Journal of clinical oncology : official journal of the American Society of Clinical Oncology, UNITED STATES, vol. 16 no. 11 (November, 1998), pp. 3570-5, ISSN 0732-183X
   (last updated on 2007/03/17)

   Abstract:
   PURPOSE: The major mechanism of resistance to alkylnitrosourea therapy is the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT), which removes chlorethylation or methylation damage from the O6-position of guanine. O6-benzylguanine (O6-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. MATERIALS AND METHODS: Patients were to be treated 18 hours before craniotomy with intravenous doses that ranged between 40 and 100 mg/m2 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 O6-BG, with a target end point of > or = 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/m2 O6-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/m2 of O6-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/m2 dose of O6-BG will be used in combination with BCNU in another phase I trial designed to determine the maximal-tolerated dose of BCNU.

   Keywords:
   Adult • Aged • Brain Neoplasms • Enzyme Inhibitors • Glioblastoma • Guanine • Humans • Middle Aged • O(6)-Methylguanine-DNA Methyltransferase • Preoperative Care • administration & dosage • administration & dosage* • analogs & derivatives* • drug therapy • enzymology • metabolism • surgery*