5-Fluorodeoxycytidine (FdC) and 5-trifluoromethyldeoxycytidine (F3methyldC), each coadministered with tetrahydrouridine (H4U), an inhibitor of cytidine deaminase (CD) are far superior to 5-fluorouracil (FUra), 5-fluorodeoxyuridine (FdU) and 5-trifluorothymidine (F3dT) in the two mouse tumor models tested, Lewis lung carcinoma and mammary adenocarcinoma-755. These prodrugs are activated by different enzymes than fluoropyrimidines currently used and unlike them, are resistant to catabolism. FdC and F3methyldC are preferentially converted in tumor to toxic nucleotides by enzymes elevated in human malignant tumors for example, dCMP deaminase is elevated 20- to 80-X in many human tumors. Due to the high CD levels in tumor, the use of moderate doses of H4U allows dual pathway activation of FdC specifically in tumors so that RNA-directed antimetabolites (FUMP) are formed to a very great extent and incorporated into RNA of tumor with little or no formation or incorporation in normal tissue, including bone marrow and intestine. Utilizing FdC + H4U, RNA level antimetabolite pools, FdU and FdUMP are generally greater than 100-fold lower in normal tissues than in tumor. In contrast, the use of FdU or FUra results in higher levels (greater than 30-fold) of DNA and RNA-directed metabolites in normal tissues and with FdU, lower levels (less than 1/20) of FdUMP, the inhibitor of thymidylate synthetase (TS), in tumor tissue than when FdC + H4U is utilized. Incorporation of analogs into nucleic acids also shows increased selectivity of FdC + H4U over FdU and FUra. The selectivity of F3methyldC is also based on moderate doses of H4U amplifying intrinsic differences between levels of CD in tumor and normal tissues. 3H-FdC and 14C-F3methyldC metabolism and pharmacokinetic will be studied. We will determine, in normal and tumor tissue, to what extent: a) human surgical tissue specimens and human tumor cell lines contain elevated levels of the relevant enzymes. In this manner we will confirm studies of others indicating that the most frequently occurring human malignant tumors (of colon, breast, lung, rectum and brain) and many human leukemias possess high levels of an enzyme(s) essential for response to our strategy, b) a limited number of human tumor cell lines display sensitivity to these dC analogs with or without H4U or dH4U, c) F3methyldCMP and F3thymine are formed in metabolite studies similar to those we have completed with adenocarcinoma-755 and Lewis lung carcinoma, d) FdUMP and F3dTMP are formed and retained, e) normal metabolite pools are affected, f) DNA synthesis and TS activity and their recovery are affected, g) F3methyldC and its metabolites are incorporated into DNA, h) FdC (and F3methyldC) incorporation affects 5-methyldC/dC ratios in DNA; that is, to what extent is DNA hypomethylated under conditions of therapy.
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