Modulation of IMP dehydrogenase activity and guanylate metabolism by tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide).
Tiazofurin, a C-nucleoside, was cytotoxic in hepatoma 3924A cells grown in culture with an LC50 = 7.5 microM. In the culture, a closely linked dose-related response of tumor cell-kill and depletion of GTP pools was observed after tiazofurin treatment. In rats carrying subcutaneously transplanted hepatoma 3924A solid tumors, a single intraperitoneal injection of tiazofurin (200 mg/kg) caused a rapid inhibition of IMP dehydrogenase (EC 1.2.1.14) activity and depleted GDP, GTP, and dGTP pools in the tumor; concurrently, the 5-phosphoribosyl 1-pyrophosphate (PRPP) and IMP pools expanded 8- and 15-fold, respectively. Tiazofurin decreased tumoral IMP dehydrogenase activity and dGTP pools in a dose-dependent manner over a range of 50-200 mg/kg; by contrast, the depletion of GTP and the accumulation of IMP and PRPP pools were near maximum at 50 mg/kg. The increase in PRPP pools may be attributed to an inhibition by IMP of the activity of hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8). The IMP dehydrogenase activity and the pools of ribonucleotides returned to the normal range by 24-48 h after the single injection of tiazofurin. However, the markedly depleted dGTP pools remained low for 72 h. Tiazofurin treatment resulted in significant anti-tumor activity in rats inoculated with hepatoma 3924A. The decrease in GTP levels and particularly the sustained depletion in the dGTP pools may explain, in part at least, the chemo-therapeutic action of tiazofurin on hepatoma 3924A. This is the first report showing that a marked therapeutic response was achieved against rapidly growing hepatoma 3924A by treatment with a single anti-metabolite.
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002460:Cell Line; D003854:Deoxyribonucleotides / Q000378:metabolism; D006150:Guanine Nucleotides / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D007168:IMP Dehydrogenase / Q000378:metabolism*; D007291:Inosine Monophosphate / Q000378:metabolism; D007658:Ketone Oxidoreductases / Q000378:metabolism*; D007700:Kinetics; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051381:Rats; D011912:Rats, Inbred ACI; D012254:Ribavirin / Q000031:analogs & derivatives / Q000633:toxicity*; D012263:Ribonucleosides / Q000633:toxicity*
D000970:Antineoplastic Agents; D003854:Deoxyribonucleotides; D006150:Guanine Nucleotides; D012263:Ribonucleosides; D007291:Inosine Monophosphate; D012254:Ribavirin; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; D007658:Ketone Oxidoreductases; C033706:tiazofurin