BACKGROUND: Efficacy of nitrosoureas is limited by host repair of drug-induced alkylation. O(6)-benzylguanine (O(6)-BG), an inhibitor of host alkylation repair, and BCNU were studied in children with refractory/untreatable central nervous system tumors to determine dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of BCNU administered following O(6)-BG. PROCEDURE: O(6)-BG (120 mg/m(2) IV over 1 hr) was followed by BCNU (IV over 1 hr). Cohorts of three to six patients were treated with escalating doses of BCNU. Courses were repeated every 6 weeks. Patients in Stage 1 were accrued irrespective of prior treatment. Once the MTD was exceeded, Stage II accrual was limited to less heavily pretreated patients (</= two prior chemotherapy regimens, no prior central axis radiation, no prior bone marrow transplant, and no bone marrow involvement). RESULTS: Twelve patients in Stage I and 13 in Stage II (less heavily pretreated patients only) were evaluable for toxicity. The MTD of BCNU administered with O(6)-BG (120 mg/m(2) IV) was 58 mg/m(2) in less-heavily pretreated patients. Myelosuppression, which was cumulative in some patients receiving multiple cycles of therapy, was the predominate DLT. Twenty-four patients were evaluable for response: after two courses of therapy, 6 had stable disease, 17 had progressive disease, and 1 patient had a minor response but progressed after four courses of therapy. CONCLUSIONS: Based on lack of activity of this combination in adult phase II studies, no further testing of O(6)-BG plus BCNU in children is planned. Strategies to decrease hematopoeitic toxicity of BCNU plus O(6)-BG are required. (c) 2007 Wiley-Liss, Inc.
BACKGROUND: Efficacy of nitrosoureas is limited by host repair of drug-induced alkylation. O(6)-benzylguanine (O(6)-BG), an inhibitor of host alkylation repair, and BCNU were studied in children with refractory/untreatable central nervous system tumors to determine dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of BCNU administered following O(6)-BG. PROCEDURE: O(6)-BG (120 mg/m(2) IV over 1 hr) was followed by BCNU (IV over 1 hr). Cohorts of three to six patients were treated with escalating doses of BCNU. Courses were repeated every 6 weeks. Patients in Stage 1 were accrued irrespective of prior treatment. Once the MTD was exceeded, Stage II accrual was limited to less heavily pretreated patients (</= two prior chemotherapy regimens, no prior central axis radiation, no prior bone marrow transplant, and no bone marrow involvement). RESULTS: Twelve patients in Stage I and 13 in Stage II (less heavily pretreated patients only) were evaluable for toxicity. The MTD of BCNU administered with O(6)-BG (120 mg/m(2) IV) was 58 mg/m(2) in less-heavily pretreated patients. Myelosuppression, which was cumulative in some patients receiving multiple cycles of therapy, was the predominate DLT. Twenty-four patients were evaluable for response: after two courses of therapy, 6 had stable disease, 17 had progressive disease, and 1 patient had a minor response but progressed after four courses of therapy. CONCLUSIONS: Based on lack of activity of this combination in adult phase II studies, no further testing of O(6)-BG plus BCNU in children is planned. Strategies to decrease hematopoeitic toxicity of BCNU plus O(6)-BG are required. (c) 2007 Wiley-Liss, Inc.
Authors: Ganesan Vaidyanathan; Benjamin White; Donna J Affleck; Darryl McDougald; Michael R Zalutsky Journal: Nucl Med Biol Date: 2010-10-27 Impact factor: 2.408
Authors: Brian C Beard; Grant D Trobridge; Christina Ironside; Jeannine S McCune; Jennifer E Adair; Hans-Peter Kiem Journal: J Clin Invest Date: 2010-06-14 Impact factor: 14.808
Authors: Narin Apisarnthanarax; Gary S Wood; Seth R Stevens; Sean Carlson; Derek V Chan; Lili Liu; Sarolta K Szabo; Pingfu Fu; Anita C Gilliam; Stanton L Gerson; Scot C Remick; Kevin D Cooper Journal: Arch Dermatol Date: 2012-05
Authors: Peter J Houghton; Christopher L Morton; Richard Gorlick; Richard B Lock; Hernan Carol; C Patrick Reynolds; Min H Kang; John M Maris; Stephen T Keir; E Anders Kolb; Jianrong Wu; Amy W Wozniak; Catherine A Billups; Larry Rubinstein; Malcolm A Smith Journal: Mol Cancer Ther Date: 2010-01-06 Impact factor: 6.261
Authors: A O von Bueren; M D Bacolod; C Hagel; K Heinimann; A Fedier; U Kordes; T Pietsch; J Koster; M A Grotzer; H S Friedman; G Marra; M Kool; S Rutkowski Journal: Br J Cancer Date: 2012-09-13 Impact factor: 7.640