Papers Published

1. HS Friedman, J Pluda, JA Quinn, RB Ewesuedo, L Long, AH Friedman, I Cokgor, OM Colvin, MM Haglund, DM Ashley, JN Rich, J Sampson, AE Pegg, RC Moschel, RE McLendon, JM Provenzale, ES Stewart, S Tourt-Uhlig, AM Garcia-Turner, JE Herndon 2nd, DD Bigner, ME Dolan, Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma., Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol. 18 no. 20 (October, 2000), pp. 3522-8, ISSN 0732-183X
   (last updated on 2013/05/16)

   Abstract:
   OBJECTIVE: 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. 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. CONCLUSIONS: 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.

   Keywords:
   Adult • Antineoplastic Combined Chemotherapy Protocols • Astrocytoma • Carmustine • Central Nervous System Neoplasms • Drug Administration Schedule • Glioblastoma • Guanine • Humans • Middle Aged • Neoplasm Recurrence, Local • administration & dosage • adverse effects • adverse effects* • analogs & derivatives* • blood • drug therapy • drug therapy* • pharmacokinetics • therapeutic use