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.