TY - JOUR
T1 - Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma
AU - Friedman, Henry S.
AU - Pluda, James
AU - Quinn, Jennifer A.
AU - Ewesuedo, Reginald B.
AU - Long, Lina
AU - Friedman, Allan H.
AU - Cokgor, Ilkcan
AU - Calvin, O. Michael
AU - Haglund, Michael M.
AU - Ashley, David M.
AU - Rich, Jeremy N.
AU - Sampson, John
AU - Pegg, Anthony E.
AU - Moschel, Robert C.
AU - McLendon, Roger E.
AU - Provenzale, James M.
AU - Stewart, Elizabeth S.
AU - Tourt-Uhlig, Sandra
AU - Garcia-Turner, Ana M.
AU - Herndon, James E.
AU - Bigner, Darell D.
AU - Dolan, M. Eileen
PY - 2000/10/15
Y1 - 2000/10/15
N2 - 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.
AB - 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.
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U2 - 10.1200/JCO.2000.18.20.3522
DO - 10.1200/JCO.2000.18.20.3522
M3 - Article
C2 - 11032594
AN - SCOPUS:0034668064
SN - 0732-183X
VL - 18
SP - 3522
EP - 3528
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 20
ER -