O6-benzylguanine-mediated enhancement of chemotherapy

Henry S. Friedman, Stephen Keir, Anthony Pegg, Peter J. Houghton, O. Michael Colvin, Robert C. Moschel, Darell D. Bigner, M. Eileen Dolan

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Abstract

We have previously demonstrated (A. E. Pegg, Cancer Res., 50: 6119-6129, 1990) that O6-benzylguanine (O6-BG) enhances nitrosourea, temozolomide, and cyclophosphamide activity in malignant glioma xenografts growing in athymic nude mice. More recently, we have demonstrated (V. J. Patel et al., Clin. Cancer Res., 6: 4154-4157, 2000; P. Pourquier et al., Cancer Res., 61: 53-58, 2001) that the combination of temozolomide plus irinotecan (CPT-11) displays a schedule-dependent enhancement of antitumor activity secondary to trapping of topoisomerase I by O6-methylguanine residues in DNA. These studies suggested that there might be favorable therapeutic interactions between O6-BG and combinations of 1,3-bis(2-chloroethyl)-1- nitrosourea (BCNU) plus cyclophosphamide or temozolomide plus CPT-11, respectively. Our present results indicate that the combination of cyclophosphamide plus BCNU plus O6-BG produces growth delays modestly-to-markedly-superior to combinations of cyclophosphamide with BCNU. Although the combination of temozolomide and CPT-11 reveals a marked increase in activity compared with either agent used alone, the addition of O 6-BG to this combination dramatically increased the growth delay of the O6-alkylguanine-DNA alkyltransferase (AGT)-positive malignant glioma D-456 MG. These results suggest that a Phase I trial of CPT-11 plus temozolomide plus O6-BG in AGT-positive tumors may be an important intervention to maximize the therapeutic benefits of the combination of CPT-11 and temozolomide.

Original languageEnglish (US)
Pages (from-to)943-948
Number of pages6
JournalMolecular cancer therapeutics
Volume1
Issue number11
StatePublished - Sep 1 2002

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Friedman, H. S., Keir, S., Pegg, A., Houghton, P. J., Colvin, O. M., Moschel, R. C., Bigner, D. D., & Dolan, M. E. (2002). O6-benzylguanine-mediated enhancement of chemotherapy. Molecular cancer therapeutics, 1(11), 943-948.