5-Trifluoromethyl-2'-deoxycytidine (F3methyl-dCyd), when coadministered with
tetrahydrouridine (H4Urd), surpasses the efficacy of 5-trifluorothymidine and
5-trifluoromethyl-2'-deoxycytidine when administered alone as demonstrated with
adenocarcinoma 755 and
Lewis lung carcinoma as solid
tumors implanted in C57BL X DBA/2 F1 mice. It appears that the reason for the heightened efficacy of F3methyl-dCyd, when coadministered with low concentrations of H4Urd, is decreased systemic deamination and subsequent systemic catabolism by
pyrimidine nucleoside phosphorylases, which do not act on
deoxycytidine and its analogues. Furthermore, the elevated levels of
cytidine deaminase in these mouse
tumors may result in selective conversion of F3methyl-dCyd to 5-trifluorothymidine at the
tumor site. This suggests an approach to the treatment of human
tumors possessing elevated levels of
cytidine deaminase such as certain
leukemias,
bronchogenic carcinoma of the
lung, adenocarcinomas of the colon and rectum,
astrocytomas, and certain
tumors which are refractory to
chemotherapy with 1-beta-D-arabinofuranosylcytosine. In contrast to fluorinated
pyrimidines in current use, F3methyl-dCyd + H4Urd potentially allows an exclusive
DNA-, rather than both
a DNA- and
RNA-, directed approach. The major mechanism of the antitumor activity of F3methyl-dCyd appears to be via inhibition by 5-trifluorothymidine-5'-monophosphate of
thymidylate synthetase, the target
enzyme of fluoropyrimidine analogues in current use. However, the established and potential differences in the mode of action, anabolism, nature of incorporation into DNA, repair and cofactor requirements of F3methyl-dCyd and its anabolites, compared to that of the commonly utilized fluorinated
pyrimidines, indicate that F3methyl-dCyd + H4Urd is a novel combination of agents. In comparative studies with
Lewis lung carcinoma, F3methyl-dCyd (+ H4Urd) was shown to surpass the efficacies of
5-fluorouracil and
5-fluorodeoxyuridine and to be essentially equal in efficacy to 5-fluorodeoxycytidine (+ H4Urd). The optimum established protocol against
Lewis lung carcinoma is F3methyl-dCyd, 175 mg/kg, + H4Urd, 25 mg/kg, once per day for 7 days. Studies utilizing high concentrations of H4Urd coadministered with F3methyl-dCyd indicate that the major pathway of
tumor inhibition is via conversion of F3methyl-dCyd to 5-trifluorothymidine in view of the fact that
tumor inhibition diminishes at doses of H4Urd which result in extensive (93%) inhibition of
tumor cytidine deaminase.(ABSTRACT TRUNCATED AT 400 WORDS)