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 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.
Friedman
Henry S
HS
Departments of Surgery, Pathology and Medicine, Duke University Medical Center, Room 047, Baker House, Trent Drive, Durham, North Carolina 27710, USA.
Keir
Stephen
S
Pegg
Anthony E
AE
Houghton
Peter J
PJ
Colvin
O Michael
OM
Moschel
Robert C
RC
Bigner
Darell D
DD
Dolan
M Eileen
ME
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D016543:Central Nervous System Neoplasms / Q000473:pathology; D003520:Cyclophosphamide / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D000077204:Temozolomide
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; D011500:Protein Synthesis Inhibitors; C064976:O(6)-benzylguanine; D006147:Guanine; D000077146:Irinotecan; D003606:Dacarbazine; D003520:Cyclophosphamide; D004247:DNA; D002330:Carmustine; D002166:Camptothecin; D000077204:Temozolomide