Effect of temozolomide and dacarbazine on O6-alkylguanine-DNA alkyltransferase activity and sensitivity of human tumor cells and xenografts to 1,3-bis(2-chloroethyl)-1-nitrosourea.
We investigated the ability of 5-(dimethyltriazeno)imidazole-4-carboxamide (DTIC, decarbazine) and an analogue, temozolomide, to deplete cells or tumors of O6-alkylguanine-DNA alkyltransferase (AGT) and to enhance the antitumor effects of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Human colon cancer (HT29) cell survival was decreased by almost 1 log when treated with 500 microM temozolomide prior to 150 microM BCNU. Administration of the maximal tolerated dose of DTIC (300 mg/kg) to nude mice carrying HT29 xenografts resulted in complete depletion of AGT activity in tumors at 4 h and 16 h. Administration of 150 mg/kg DTIC caused a 76% reduction in AGT activity at 4 h, but only a 28% reduction at 16 h. The maximally tolerated doses of DTIC and BCNU, alone and in combination, were used to treat nude mice bearing HT29 xenografts. No difference in tumor growth occurred when animals were treated with either BCNU alone (50 mg/kg), DTIC alone (300 mg/kg), DTIC (150 mg/kg) followed by BCNU (12.5 mg/kg), or BCNU (25 mg/kg) followed by DTIC (150 mg/kg). These data suggest that methylating agents such as DTIC may be too toxic to be used in combination with BCNU to deplete tumor alkyltransferase levels effectively and increase the therapeutic index of BCNU.
Mitchell
R B
RB
Department of Medicine, University of Chicago, IL 60637.
Dolan
M E
ME
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002330:Carmustine / Q000008:administration & dosage / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003606:Dacarbazine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine; D000077204:Temozolomide