Enzymatic cleavage of various fluorinated pyrimidine nucleosides to 5-fluorouracil and their antiproliferative activities in human and murine tumor cells.

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The antitumor agent 5'-deoxy-5-fluorouridine (5'-dFUrd) is a prodrug from which 5-fluorouracil (5-FUra) is generated mainly by uridine phosphorylase in mice and by thymidine phosphorylase in human tumors. In the present study varios derivatives related to 5'-dFUrd were examined to establish the relationship between their susceptibilities to these enzymes, and their in vitro antitumor activities against both human and murine tumor cells. These studies divided the compounds into four distinct groups. 1) Compounds (including 5'-dFUrd) which were phosphorolyzed to 5-FUra by extracts from both human tumors and murine sarcoma 180; these compounds inhibited the growth of both murine (sarcoma 180 and B16 melanoma) and human (HeLa and G361 melanoma) cells. 2) Compounds which were phosphorolyzed only by the extract from the murine tumor; these compounds inhibited the growth of only the murine tumor cells. 3)Compounds phosphorolyzed only by the human tumor extracts; these compounds showed activity against the tumor cells of both species, although the relative activity against the human tumor cells appeared to be higher than that of group 1 compounds. 4) Compounds which were not phosphorolyzed by the extracts from the human or murine tumors; these compounds showed no antitumor activity. These results suggest that phosphorolysis of the 5'-dFUrd analogs is essential for antitumor activity, and that the metabolism of pyrimidine nucleosides is different between human and mouse tumors. Future approaches towards the design of prodrugs of 5-FUra and 5'-dFUrd should be aimed at compounds which generate 5-FUra in human tumor cells, or which are substrates for the human enzyme.