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Metabolism and Biological Activity of 5'-Deoxy-5-Fluorouridine, a Novel Fluoropyrimidine¹

Department of Pharmacology and Medicine, Medical College of Virginia, Richmond, Virginia 23298

5'-Deoxy-5-fluorouridine (5'-dFUrd; Roche 21-9738) is a recently synthesized antineoplastic agent with therapeutic potential. The sensitivity of Ehrlich ascites tumor cells in CF-1 mice to 5'-dFUrd, as well as to 5-fluorouracil (FUra), 5-fluoro-2'-deoxyuridine, and 5-fluorouridine, was established. 5'-dFUrd was a more effective antitumor agent and was less toxic over a wide dosage range (50 to 400 mg/kg) than the other agents tested as measured by: (a) the ability to prevent gross development of inoculated tumor; (b) 45-day survival; and (c) weight change over the treatment period. With use of these sensitive tumor cells, the intracellular metabolism of 5'-dFUrd in vitro was investigated. Utilizing liquid chromatographic methodology for separation of acid-soluble metabolites, the only detectable metabolic products of 5'-dFUrd were FUra, 5-fluorouridine 5'-monophosphate, and 5-fluorouridine 5'-triphosphate. Novel metabolites of 5'-dFUrd were not detectable in the acid-soluble fraction or in plasma isolated from mice given [¹⁴C]5'-dFUrd. The formation of FUra appears to result from the action of nucleoside phosphorylase. 5'-dFUrd was shown to have a K_m of 0.633 mM for this enzyme isolated from Ehrlich ascites tumor cells, an affinity similar to that for 5-fluoro-2'-deoxyuridine (K_m, 0.278 mM) but much lower than that for 5-fluorouridine (K_m, 0.049 mM). Incorporation of radiolabeled drug into the acid-insoluble fraction (representing greater than 95% incorporation into RNA) was also significant. 5-Fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) was not detectable as an acid-soluble metabolite. However, significant inhibition of thymidylate synthetase activity was detectable by 20 min in cells incubated with 30 µM 5'-dFUrd, suggesting that FdUMP was produced. The production of both 5-fluorouridine 5'-triphosphate and FdUMP appears dependent on the initial expansion of the FUra pool. This correlates with the inability of 5'-dFUrd to form nucleotide directly due to the absence of a 5'-hydroxyl group.

It is concluded that the antineoplastic activity of 5'-dFUrd may be dependent on its enzymatic conversion to FUra. The basis for the possible increase in therapeutic index compared with other fluoropyrimidines may involve the rate and duration of the production of the biologically active nucleotides 5-fluorouridine 5'-triphosphate and FdUMP.

¹ Presented in part at the 17th Annual Meeting of the American Association for Cancer Research, New Orleans, La., May 16 to 19, 1979 (1). This study was supported in part by Grant IN-105D from the American Cancer Society, a Grant from Hoffman-LaRoche Inc., and Public Health Service Research Grant CA 23412.

² To whom requests for reprints should be addressed.

Received 10/12/79. Accepted 6/ 6/80.

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