O6-benzylguanine-mediated enhancement of chemotherapy.

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 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.

• Authors: Henry S Friedman, Stephen Keir, Anthony E Pegg, Peter J Houghton, O Michael Colvin, Robert C Moschel, Darell D Bigner, M Eileen Dolan
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 1 Issue 11 Pg. 943-8 (Sep 2002) ISSN: 1535-7163 [Print] United States
• PMID: 12481416 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Antineoplastic Agents, Alkylating
• Enzyme Inhibitors
• Protein Synthesis Inhibitors
• O(6)-benzylguanine
• Guanine
• Irinotecan
• Dacarbazine
• Cyclophosphamide
• DNA
• Carmustine
• Camptothecin
• Temozolomide

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Antineoplastic Agents, Alkylating (pharmacology)
• Camptothecin (analogs & derivatives, pharmacology)
• Carmustine (pharmacology)
• Central Nervous System Neoplasms (pathology)
• Cyclophosphamide (pharmacology)
• DNA (metabolism)
• Dacarbazine (analogs & derivatives, pharmacology)
• Enzyme Inhibitors (pharmacology)
• Female
• Guanine (analogs & derivatives, pharmacology)
• Humans
• Irinotecan
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Transplantation
• Protein Synthesis Inhibitors (pharmacology)
• Temozolomide