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Departments of Surgery [H. S. F., S. K., D. D. B.], Pathology [H. S. F., D. D. B.], and Medicine [H. S. F., O. M. C., D. D. B.], Duke University Medical Center, Durham, North Carolina 27710; Department of Cellular and Molecular Physiology, The Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033 [A. E. P.]; Department of Molecular Pharmacology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38101 [P. J. H.]; Laboratory of Comparative Carcinogenesis, National Cancer Institute of Frederick, Frederick, Maryland 21702 [R. C. M.]; and Department of Medicine, University of Chicago, Chicago, Illinois 60637 [M. E. D.]

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 O⁶-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.

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