| Phase 1 trial of O6-benzylguanine and BCNU in children with CNS tumors: a Children's Oncology Group study. | |
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MedLine Citation:
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PMID: 17941066 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Denise M Adams; Tianni Zhou; Stacey L Berg; Mark Bernstein; Kathleen Neville; Susan M Blaney; |
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Publication Detail:
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Type: Clinical Trial, Phase I; Journal Article; Multicenter Study; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Pediatric blood & cancer Volume: 50 ISSN: 1545-5017 ISO Abbreviation: Pediatr Blood Cancer Publication Date: 2008 Mar |
Date Detail:
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Created Date: 2008-01-15 Completed Date: 2008-02-12 Revised Date: 2009-01-12 |
Medline Journal Info:
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Nlm Unique ID: 101186624 Medline TA: Pediatr Blood Cancer Country: United States |
Other Details:
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Languages: eng Pagination: 549-53 Citation Subset: IM |
Copyright Information:
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(c) 2007 Wiley-Liss, Inc. |
Affiliation:
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Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA. Denise.Adams@cchmc.org |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adolescent Antineoplastic Agents, Alkylating / administration & dosage, adverse effects, pharmacology* Antineoplastic Combined Chemotherapy Protocols / adverse effects, therapeutic use* Bone Marrow Diseases / chemically induced Carmustine / administration & dosage, adverse effects, pharmacology* Central Nervous System Neoplasms / drug therapy*, therapy Child Child, Preschool Cohort Studies Combined Modality Therapy DNA Repair / drug effects DNA, Neoplasm / drug effects Enzyme Inhibitors / administration & dosage, pharmacology, therapeutic use Female Guanine / administration & dosage, adverse effects, analogs & derivatives*, pharmacology Humans Male Maximum Tolerated Dose Neoplasm Proteins / antagonists & inhibitors* O(6)-Methylguanine-DNA Methyltransferase / antagonists & inhibitors* Salvage Therapy |
| Grant Support | |
ID/Acronym/Agency:
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CA 97543/CA/NCI NIH HHS; M01 RR00188/RR/NCRR NIH HHS; U01 CA97552/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents, Alkylating; 0/DNA, Neoplasm; 0/Enzyme Inhibitors; 0/Neoplasm Proteins; 154-93-8/Carmustine; 19916-73-5/O(6)-benzylguanine; 73-40-5/Guanine; EC 2.1.1.63/O(6)-Methylguanine-DNA Methyltransferase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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