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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Friedman, HS; Kokkinakis, DM; Pluda, J; Friedman, AH; Cokgor, I; Haglund, MM; Ashley, DM; Rich, J; Dolan, ME; Pegg, AE; Moschel, RC; McLendon, RE; Kerby, T; Herndon, JE; Bigner, DD; Schold, SC

Published Date

  • November 1998

Published In

Volume / Issue

  • 16 / 11

Start / End Page

  • 3570 - 3575

PubMed ID

  • 9817277

Pubmed Central ID

  • 9817277

International Standard Serial Number (ISSN)

  • 0732-183X

Digital Object Identifier (DOI)

  • 10.1200/JCO.1998.16.11.3570

Language

  • eng

Conference Location

  • United States