Tiazofurin action in leukemia: evidence for down-regulation of oncogenes and synergism with retinoic acid.

New light was thrown on the action of tiazofurin in the treatment of end-stage leukemic patients and in leukemic cells in tissue culture. 1. In a population of 21 consecutive patients 50% responded to tiazofurin treatment, confirming the usefulness of this therapy in end-stage leukemia. 2. In leukemic patients treated with tiazofurin and allopurinol reciprocal action was manifested in the increase in hypoxanthine and the decrease in uric acid concentrations in the plasma. On discontinuation of allopurinol, hypoxanthine levels steeply declined but uric acid concentration increased slowly, taking days to reach pretreatment level. 3. With a new and sensitive method the concentration of the active metabolite of tiazofurin, TAD, was measured in the mononuclear cells of tiazofurin-treated patients. Approximately 5 to 13% of the plasma tiazofurin level was observed as TAD in the mononuclear cells. This TAD concentration was sufficient to account for the inhibition of IMP DH in these cells. 4. Tiazofurin or retinoic acid caused differentiation of HL-60 leukemic cells and inhibition of cell proliferation. 5. By treating leukemic cells incubated with tiazofurin or retinoic acid also with guanosine it was elucidated that the mechanism of the two drugs differed since only the tiazofurin effects were counteracted by guanosine. 6. Tiazofurin and retinoic acid together in HL-60 cells provided synergistic impact on differentiation and cytotoxicity. 7. Tiazofurin resulted in down-regulation of the expression of ras and myc oncogenes in three systems: K562 human erythroleukemic cells, rat hepatoma 3924A cells and human HL-60 leukemia cells. 8. Because both tiazofurin and retinoic acid are licensed drugs, their potential use in combination chemotherapy may have clinical relevance in the treatment of end-stage leukemia where our earlier studies have demonstrated the usefulness of tiazofurin.