Studies on fluorinated pyrimidines. IV. Effects on nucleic acid metabolism in vivo.

作者：P B DANNEBERG, B J MONTAG, Charles Heidelberger · 发表于：PubMed · 年份：1958 · 被引用次数：262 · 研究领域：Biochemical and Molecular Research、Mycobacterium research and diagnosis、Cancer therapeutics and mechanisms

Summary 1.A study of the effects of fluorinated pyrimidines on nucleic acid biosynthesis has been carried out in suspensions of Ehrlich ascites cells incubated anaerobically with various labeled substrates. The drugs did not inhibit glycolysis. 2.The conversion of formate-C14 into DNA thymine was inhibited in increasing order of potency by 5-fluoroorotic acid, 5-fluorouracil, 5-fluorouridine, and 5-fluoro-2′-deoxyuridine. This inhibition by 5-fluorouracil and 5-fluoroorotic acid was reversed by deoxyuridine. However, formate incorporation into nucleic acid adenine was not inhibited. 3.In studies of permeability it was found that 5-fluorouracil was taken up by the ascites cells to a greater extent than were uracil, orotic acid, and fluoroorotic acid. 5-Fluorouridine caused an increased cellular uptake of uracil and orotic acid. 4.The fluorinated pyrimidines did not affect the conversion of thymidine-6-H3 into DNA thymine, nor the incorporation of phosphate-P32 into DNA or RNA in these cell suspensions. 5.The fluorinated pyrimidines inhibited the metabolic conversion of uracil-2-C14 and orotic-6-C14 acid into DNA thymine and, with the exception of 5-fluoro-2′-deoxyuridine, inhibited the incorporation of the same precursors into RNA uracil. The metabolic transformation of uracil and orotic acid into nucleic acid cytosine was not greatly affected by the drugs. 6.5-Fluorouracil-2-C14 was converted into 5-fluoro-2′-deoxyuridine monophosphate and was also incorporated as such into R...