TIAZOFURIN ENHANCES THE ANABOLISM AND TOXICITY OF 5-FLUOROURACIL

Tiazofurin, a clinically active anticancer agent, is undergoing additi onal clinical testing in combination with other agents. We found that tiazofurin is an effective biochemical modulator of 5-fluorouracil ana bolism. Pretreatment of cultured L1210 cells with tiazofurin at concen trations of 1-100 mu M results in an increase in the rate of conversio n of 5-fluorouracil to phosphorylated metabolites. Concentrations of t iazofurin effective in increasing 5-fluorouracil anabolism cause a cor responding increase in the 5-phosphoribosyl-1-pyrophosphate pool. Stud ies in mice show that tiazofurin increases the lethal toxicity of 5-fl uorouracil and increases the antitumor effectiveness of low doses of 5 -fluorouracil; however, the combination is not more effective than an optimal dose of 5-fluorouracil given alone. These results indicate tha t caution should be exercised in the concurrent use of tiazofurin with other drugs, particularly 5-fluorouracil, that require 5-phosphoribos yl-1-pyrophosphate for activation or that are affected by a decrease i n pyrimidine nucleotide synthesis.