Comparative studies of fluorinated pyrimidines with various cell lines.

pound (1 7) with useful clinical activity ( 16), a wide variety of pyrimidines and nucleoside analogs of various types have been synthesized and their biologic and biochemical activities de scribed. This laboratory has been engaged in the synthesis and study of a number of other fluorinated pyrimidines (cf 14), among which the most interesting are FUR, FUDR (14), and F3TDR (18). Recently we have reported the synthesis and tumor-inhibitory activity of DHFUDR, together with an out line of some of its biochemical and mechanistic features (23). IUDR, an antimetabolite with weak tumor-inhibitory proper ties (2), has been found to have powerful therapeutic antiviral activity against herpes simplex keratitis (22), as does F3TDR (21), which is also an effective tumor-inhibitory compound (15). ara-C was introduced as a tumor-inhibitor (7) and also is active against herpes simplex keratitis (36). As has been extensively reviewed (14), the mechanism of action of members of the FU series involves conversion to the nucleotide (FUDRP), which blocks DNA synthesis as a conse quence of the inhibition of thymidylate synthetase (6, 12, 29). There is also incorporation into RNA (14), but the biologic consequences of this pathway are not clear (cf 1). The nucleo tide of F3TDR (14) not only inhibits thymidylate synthetase (29), but is also incorporated into DNA of bacteriophage T4 and mammalian cells (1 1). IUDR is incorporated into DNA, without inhibiting thymidylate synthetase, but inhibits several other enzymes of nucleic acid biosynthesis (28). ara-C also inhibits DNA synthesis, but its primary site of action and the reality or degree of its incorporation into DNA have not yet been clearly established (3—5,25, 33). Unlike FUDR and IUDR, DHFUDR (23), although a power ful inhibitor of tumor growth, is not phosphorylated to the nucleotide by thymidine kinase. Therefore, it appeared that DHFUDR should be active against cells and tumors that are resistant to FUDR because of a loss of thymidine kinase . In the present study, this possibility was examined in conjunction with a systematic comparative study of the effects of the above-mentioned pyrimidine nucleoside analogs on the growth of several cell lines in culture, and possible prevention of the inhibition by the appropriate normal metabolites was deter mined.