O⁶-benzylguanine-mediated enhancement of chemotherapy

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.