Tiazofurin enhances the anabolism and toxicity of 5-fluorouracil.
Tiazofurin, a clinically active anticancer agent, is undergoing additional clinical testing in combination with other agents. We found that tiazofurin is an effective biochemical modulator of 5-fluorouracil anabolism. Pretreatment of cultured L1210 cells with tiazofurin at concentrations of 1-100 microM results in an increase in the rate of conversion of 5-fluorouracil to phosphorylated metabolites. Concentrations of tiazofurin effective in increasing 5-fluorouracil anabolism cause a corresponding increase in the 5-phosphoribosyl-1-pyrophosphate pool. Studies in mice show that tiazofurin increases the lethal toxicity of 5-fluorouracil 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 that caution should be exercised in the concurrent use of tiazofurin with other drugs, particularly 5-fluorouracil, that require 5-phosphoribosyl-1-pyrophosphate for activation or that are affected by a decrease in pyrimidine nucleotide synthesis.
Cysyk
R L
RL
Laboratory of Medicinal Chemistry, National Cancer Institute, Bethesda, MD, USA.
Chisena
C A
CA
Hyman
R
R
Monks
A
A
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D005472:Fluorouracil / Q000378:metabolism* / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism*; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D012254:Ribavirin; D010754:Phosphoribosyl Pyrophosphate; D005472:Fluorouracil; C033706:tiazofurin