THE MODE OF ACTION OF 5-FLUOROURACIL AND ITS DERIVATIVES

Abstract

The inhibitory actions of 5-fluorouracil and its nucleosides on growth and multiplication were studied in Escherichia coli and a series of pyrimidine-requiring strains of this organism. The effects noted on uracil metabolism were related to growth inhibition but not survival while the effects noted on thymine metabolism indicate that a thymine deficiency is markedly bactericidal. Of the compounds tested, fluorouracil deoxyriboside was maximally potent in its bactericidal activity. Fluorouracil deoxyriboside is assimilated by bacteria and is converted partially to the deoxyribotide which has been isolated. Fluorouracil dexoyribotide was also synthesized enzymatically from fluorouracil deoxyriboside to yield a product identical with the synthetic 5[image]-dexoyribotide. 5[image]-dexoyribotide is a highly potent irreversible inhibitor of thymidylate synthetase. This effect explains the capability of fluorouracil and its deoxyriboside to create thymine deficiency.