Antitumor activity of FTC-092, a masked 5-trifluoromethyl-2′-deoxyuridine derivative

Summary

1-(3-O-Benzyl-2-deoxy-β-d-ribofuranosyl)-5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (FTC-092), a fluorinated pyrimidine derivative, appeared to be effective against various transplantable tumors in mice following oral administration, and its activity was superior to that of several other antitumor fluorinated pyrimidines. The ED₅₀ value for FTC-092 the dose effective in achieving 50% inhibition of tumor growth against the solid form of sarcoma 180 was 13.3 mg/kg daily, whereas those for 5-trifluoromethyl-2′-deoxyuridine (CF₃dUrd), the parent compound of FTC-092, for 1-(2-tetrahydrofuryl)-5-fluorouracil (Tegafur, FT), the prodrug of 5-fluorouracil (FUra), and for FUra were 64.1, 122, and 28 mg/kg daily, respectively. The therapeutic indices (LD₁₀/ED₅₀) of FTC-092, CF₃dUrd, FT, and FUra were 4.39, 1.7, 1.35, and 1.65, respectively. FTC-092 itself is not an active agent. After it has been absorbed from the gastrointestinal tract, FTC-092 undergoes a gradual biotransformation, mainly via the action of liver microsomes, releasing CF₃dUrd over a long period. The levels of CF₃dUrd in the stomach and small intestine of mice after the oral administration of FTC-092 were undetectable, whereas those following the administration of CF₃dUrd at the same dose were high for a period of several hours. In contrast, the CF₃dUrd level generated in plasma after the administration of FTC-092 remained at a high level for a longer period than did that observed on the administration of CF₃dUrd. The low levels of CF₃Urd measured in stomach and small-intestine tissues and the maintenance of CF₃dUrd in blood over long periods after the administration of FTC-092 are features that favor the possible clinical application of FTC-092.