The emerging role of irinotecan (CPT-11) in the treatment of malignant glioma in brain tumors.
Irinotecan is a water-soluble derivative of camptothecin, an alkylator originally extracted from the Chinese tree Camptotheca acuminata. Laboratory studies have demonstrated the activity of irinotecan in a broad panel of pediatric and adult central nervous system tumor xenografts in athymic nude mice. These studies led to a Phase II trial that confirmed the activity of this agent in the treatment of recurrent malignant glioma. Subsequent laboratory studies have demonstrated that a combination of irinotecan (CPT-11) and alkylating agents, particularly 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), increases antitumor effects to a level well above the additive effects of the individual agents. These laboratory studies generated a recently completed Phase I trial of CPT-11 + BCNU, which now is being evaluated in a formal Phase II trial for adults with newly diagnosed or recurrent malignant glioma. More recent studies have demonstrated similar interaction between CPT-11 and temozolomide and have led to a Phase I trial of these agents in the treatment of adults with malignant glioma. Studies currently are addressing the role of O(6)-alkylguanine-DNA alkyltransferase (AGT) in reducing the benefits of combining CPT-11 with temozolomide and the potential therapeutic gain from utilizing an inhibitor of AGT.
Friedman
Henry S
HS
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA. fried003@mcduke.edu
Keir
Stephen T
ST
Houghton
Peter J
PJ
D000328:Adult; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D002330:Carmustine / Q000008:administration & dosage; D002986:Clinical Trials as Topic; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D000077146:Irinotecan; D009364:Neoplasm Recurrence, Local; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D003606:Dacarbazine; D002330:Carmustine; D002166:Camptothecin; D000077204:Temozolomide