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The Antineoplastic and Biochemical Effects of Some 5-Fluoropyrimidines¹

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510

The comparative growth-inhibitory activities of 5-fluorouracil (5-FU), 4-hydroxy-5-fluoropyrimidine (4-HFP), and 2-hydroxy-5-fluoropyrimidine (2-HFP) were measured on Sarcoma 180 ascites cells. A marked extension of the life-span of tumor-bearing mice was afforded by i.p. injections of 5-FU, whereas both 4-HFP and 2-HFP were only weakly active. Sarcoma 180 ascites cells converted both 4-HFP and 5-FU into mono-, di-, and trinucleotide forms of 5-FU and incorporated the 5-fluoropyrimidines into RNA exclusively as 5-FU. Mice given i.p. injections of 4-HFP excreted the compound into the urine primarily as 5-FU and its metabolites. The incorporation of formate-¹⁴C into the thymine of DNA was inhibited by 5-FU, 4-HFP, and 2-HFP; measurement of the duration of inhibition by molar equivalent doses of these agents indicated that the longevity of blockade was greatest with 5-FU, while that caused by 2-HFP was the shortest. Administration of an inhibitor of the activity of xanthine oxidase, 4-hydroxypyrazolo(3,4-d)pyrimidine, reduced not only the slight tumor inhibition and toxicity produced by 4-HFP, but also the conversion of this agent to 5-FU and its metabolites and the degree of inhibition of the incorporation of formate-¹⁴C into DNA, suggesting that in order to manifest biologic and biochemical activity, 4-HFP must be converted to 5-FU. The incorporation of formate-¹⁴C and hypoxanthine-8-¹⁴C into the guanine of the nucleic acids was inhibited by 5-FU, whereas the utilization of these isotopic substrates for the formation of nucleic acid adenine was unaffected. The incorporation of guanine-8-¹⁴C into the guanine and adenine of the nucleic acid also was insensitive to the action of 5-FU, suggesting the presence of a 5-FU-sensitive site on the pathway from inosine 5'-phosphate to guanosine 5'-phosphate. The possible significance of these findings is discussed.

¹ This research was supported by Grant CA-02817 from the National Cancer Institute, USPHS, and by Grant T-335B from the American Cancer Society. Presented in part at the 152nd Meeting of the American Chemical Society, New York, September, 1966.

Received 3/15/67. Accepted 7/12/67.