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

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.

• Authors: H S Friedman, D M Kokkinakis, J Pluda, A H Friedman, I Cokgor, M M Haglund, D M Ashley, J Rich, M E Dolan, A E Pegg, R C Moschel, R E McLendon, T Kerby, J E Herndon, D D Bigner, S C Schold Jr
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 16 Issue 11 Pg. 3570-5 (Nov 1998) ISSN: 0732-183X [Print] United States
• PMID: 9817277 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enzyme Inhibitors
• O(6)-benzylguanine
• Guanine
• O(6)-Methylguanine-DNA Methyltransferase

Topics

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