Journal of Clinical Oncology, Vol 16, 3570-3575, Copyright © 1998 by American Society of Clinical Oncology
Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma
HS Friedman, DM Kokkinakis, J Pluda, AH Friedman, I Cokgor, MM Haglund, DM Ashley, J Rich, ME Dolan, AE Pegg, RC Moschel, RE McLendon, T Kerby, JE Herndon, DD Bigner and SC Schold Jr
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
PURPOSE: The major mechanism of resistance to alkylnitrosourea therapy is
the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT), which
removes chlorethylation 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 to define the
presurgical dose required for depletion of tumor AGT activity in patients
with malignant glioma. MATERIALS AND METHODS: Patients were to be treated
18 hours before craniotomy with intravenous doses that ranged between 40
and 100 mg/m2 given over 1 hour. Resected tumor was snap-frozen in liquid
nitrogen and AGT activity analyzed by high-pressure liquid chromatography
(HPLC). Up to 13 patients were treated at a specific dose of O6-BG, with a
target end point of > or = 11 of 13 patients with undetectable tumor AGT
levels (< 10 fmol/mg protein). RESULTS: Thirty patients with malignant
gliomas were enrolled, with 11 of 11 patients treated at 100 mg/m2 O6-BG
demonstrating tumor AGT levels less than 10 fmol/mg protein. No toxicity
was noted in any patient treated. CONCLUSION: These results indicate that
100 mg/m2 of O6-BG can maintain tumor AGT levels less than 10 fmol/mg
protein for at least 18 hours after treatment, a time interval in which
bis(2-chloroethyl)nitrosourea (BCNU)-induced chloroethyl adducts are fully
converted into interstrand cross-links. A 100-mg/m2 dose of O6-BG will be
used in combination with BCNU in another phase I trial designed to
determine the maximal-tolerated dose of BCNU.
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H. S. Friedman
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[Full Text]
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[Full Text]
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[Abstract]
[Full Text]
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D. M. Kokkinakis, R. C. Moschel, A. E. Pegg, and S. C. Schold
Eradication of Human Medulloblastoma Tumor Xenografts with a Combination of O6-Benzyl-2'-deoxyguanosine and 1,3-Bis(2-chloroethyl)-1-nitrosourea
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[Abstract]
[Full Text]
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M. Xu-Welliver, J. Leitao, S. Kanugula, and A. E. Pegg
Alteration of the Conserved Residue Tyrosine-158 to Histidine Renders Human O6-Alkylguanine-DNA Alkyltransferase Insensitive to the Inhibitor O6-Benzylguanine
Cancer Res.,
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[Abstract]
[Full Text]
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M. H. Wu, K. E. Lohrbach, O. I. Olopade, D. M. Kokkinakis, H. S. Friedman, and M. E. Dolan
Lack of Evidence for a Polymorphism at Codon 160 of Human O6-Alkylguanine-DNA Alkyltransferase Gene in Normal Tissue and Cancer
Clin. Cancer Res.,
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209 - 213.
[Abstract]
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