Antitumor activity of tiazofurin in human colon carcinoma HT-29.
Tiazofurin is effective in treating end-stage leukemic patients (Tricot et al., Cancer Res 49:3696-3701, 1989). In sensitive tumors, the active metabolite of tiazofurin, TAD, potently inhibits IMP dehydrogenase activity, resulting in reduced guanylate pools. To elucidate tiazofurin activity in human solid tumors, we examined its activity in human colon carcinoma HT-29. Tiazofurin exhibited an LC50 of 35 microM in cultured HT-29 cells. Incubation of HT-29 cells with 100 microM tiazofurin for 2 h resulted in TAD formation (9.3 nmol/g cells) and in a 64% decrease in GTP pools. For biochemical and chemotherapy studies, athymic nude mice were transplanted s.c. with HT-29 cells. Twenty-four days later, mice were injected i.p. with tiazofurin (500 mg/kg); 6 h later, tumors were removed and analyzed. These tumors formed 17 nmol/g of TAD with decreased GTP pools (56%). To study oncolytic activity, transplanted mice were treated 24 h later with tiazofurin (500 mg/kg, once a day for 10 days). To examine the effectiveness of tiazofurin in established tumors, the drug was administered to mice 14 days after tumor implantation (500 mg/kg, once a day for 5 days, course repeated 4 times with a 10-day rest). Both treatment schedules resulted in significant antitumor activity. This study illustrates the potential usefulness of tiazofurin in treating human colon carcinoma.
Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46202-5200.
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Zhen
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Jayaram
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Weber
D000227:Adenine Nucleotides / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D012254:Ribavirin; C038167:thiazole-4-carboxamide adenine dinucleotide; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; C033706:tiazofurin