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

Henry S. Friedman, Demetrius M. Kokkinakis, James Pluda, Allan H. Friedman, Ilkcan Cokgor, Michael M. Haglund, David M. Ashley, Jeremy Rich, M. Eileen Dolan, Anthony Pegg, Robert C. Moschel, Roger E. McLendon, Tracy Kerby, James E. Herndon, Darell D. Bigner, S. Clifford Schold

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Abstract

Purpose: The major mechanism of resistance to alkyl-nitrosourea 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 ≥ 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.

Original languageEnglish (US)
Pages (from-to)3570-3575
Number of pages6
JournalJournal of Clinical Oncology
Volume16
Issue number11
DOIs
StatePublished - Jan 1 1998

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Friedman, H. S., Kokkinakis, D. M., Pluda, J., Friedman, A. H., Cokgor, I., Haglund, M. M., Ashley, D. M., Rich, J., Dolan, M. E., Pegg, A., Moschel, R. C., McLendon, R. E., Kerby, T., Herndon, J. E., Bigner, D. D., & Schold, S. C. (1998). Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma. Journal of Clinical Oncology, 16(11), 3570-3575. https://doi.org/10.1200/JCO.1998.16.11.3570