Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma

Henry S. Friedman, James Pluda, Jennifer A. Quinn, Reginald B. Ewesuedo, Lina Long, Allan H. Friedman, Ilkcan Cokgor, O. Michael Calvin, Michael M. Haglund, David M. Ashley, Jeremy N. Rich, John Sampson, Anthony E. Pegg, Robert C. Moschel, Roger E. McLendon, James M. Provenzale, Elizabeth S. Stewart, Sandra Tourt-Uhlig, Ana M. Garcia-Turner, James E. HerndonDarell D. Bigner, M. Eileen Dolan

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

Abstract

Purpose: The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation 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 of carmustine (BCNU) plus O6-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O6-BG with recurrent or progressive malignant glioma. Patients and Methods: Patients were treated with O6-BG at a dose of 100 mg/m2 followed 1 hour later by BCNU. Cohorts of three to six patients were treated with escalating doses of BCNU, and patients were observed for at least 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O6-BG, 8-oxo-O6-BG, and 8-oxoguanine concentration. Results: Twenty-three patients were treated (22 with glioblastoma multiforme and one with anaplastic astrocytoma). Four dose levels of BCNU (13.5, 27, 40, and 55 mg/m2) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O6-BG rapidly disappeared from plasma (elimination half-life = 0.54 ± 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O6-BG (elimination half-life = 5.6 ± 2.7 hours) and further to 8-oxoguanine. There was no detectable O6-BG 5 hours after the start of the O6-BG infusion; however, 8-oxo-O6-BG and 8-oxoguanine concentrations were detected 25 hours after O6-BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O6-BG was 17.5 times greater than the mean AUC for O6-BG. Conclusion: These results indicate that the MTD of BCNU when given in combination with O6-BG at a dose of 100 mg/m2 is 40 mg/m2 administered at 6-week intervals. This study provides the foundation for a phase II trial of O6-BG plus BCNU in nitrosourea-resistant malignant glioma. (C) 2000 by American Society of Clinical Oncology.

Original languageEnglish (US)
Pages (from-to)3522-3528
Number of pages7
JournalJournal of Clinical Oncology
Volume18
Issue number20
DOIs
StatePublished - Oct 15 2000

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Phase I trial of carmustine plus O<sup>6</sup>-benzylguanine for patients with recurrent or progressive malignant glioma'. Together they form a unique fingerprint.

Cite this