Tiazofurin: molecular and clinical action.

UNLABELLED

The purpose is to provide an overview of the molecular and clinical impact of tiazofurin.

METHOD

The biochemical and clinical techniques were reported (1, 2).

RESULTS

IMP DH activity increased in various animal and human tumors and was particularly high in leukemic blast cells. The increased activity was due to an elevation in the mRNA concentration of type II isozyme. Tiazofurin, a C-nucleoside, was converted in sensitive cells to the active metabolite, TAD, which tightly bound at the NADH site inhibited IMP DH activity. The inhibition led to decreased GTP concentration, down-regulation of ras and myc oncogenes and induced maturation of blast cells. New evidence shows that tiazofurin injection downregulated signal transduction activity due to a reduction of the activities of PI and PIP kinases leading to a decrease in the concentration of the second messenger, IP3. In patients; tiazofurin infusion and allopurinol administration led to reduction of IMP DH activity and GTP concentration. Allopurinol inhibited xanthine oxidase activity leading to a marked rise in hypoxanthine concentration which inhibited the increased guanine salvage pathway. In the clinic, the increase in serum hypoxanthine concentration is essential for the success of tiazofurin treatment. Tiazofurin showed additivity or synergism with ribavirin, retinoic acid, taxol, quercetin, gemcitabin, dipyridamole and brefeldin. Ribavirin which inhibits IMP DH at the IMP site has been shown to prolong the IMP depressing action of tiazofurin in rat bone marrow cells.

CONCLUSION

Tiazofurin and allopurinol achieve reduction of GTP concentration in leukemic blast cells through inhibition of IMP DH and GPRT activities. As a result, induced maturation occurs with down-regulation of ras and myc oncogenes and probably reduced signal transduction capacity. Tiazofurin in leukemic patients provides over 75% therapeutic responses and patients can be treated with this combination for many months with good quality of life. These clinical and biochemical results were recently confirmed independently (3).