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Phase I Trial of Carmustine Plus O6-Benzylguanine for Patients With Recurrent or Progressive Malignant Glioma

2000; Lippincott Williams & Wilkins; Volume: 18; Issue: 20 Linguagem: Inglês

10.1200/jco.2000.18.20.3522

1527-7755

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

DNA Repair Mechanisms

PURPOSE: The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O 6 -alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O 6 position of guanine. O 6 -benzylguanine (O 6 -BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O 6 -BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O 6 -BG with recurrent or progressive malignant glioma. PATIENTS AND METHODS: Patients were treated with O 6 -BG at a dose of 100 mg/m 2 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 O 6 -BG, 8-oxo-O 6 -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/m 2 ) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O 6 -BG rapidly disappeared from plasma (elimination half-life = 0.54 ± 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O 6 -BG (elimination half-life = 5.6 ± 2.7 hours) and further to 8-oxoguanine. There was no detectable O 6 -BG 5 hours after the start of the O 6 -BG infusion; however, 8-oxo-O 6 -BG and 8-oxoguanine concentrations were detected 25 hours after O 6 -BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O 6 -BG was 17.5 times greater than the mean AUC for O 6 -BG. CONCLUSION: These results indicate that the MTD of BCNU when given in combination with O 6 -BG at a dose of 100 mg/m 2 is 40 mg/m 2 administered at 6-week intervals. This study provides the foundation for a phase II trial of O 6 -BG plus BCNU in nitrosourea-resistant malignant glioma.