5-Trifluoromethyl-2'-deoxycytidine (F3methyl-dCyd), when coadministered with tetrahydrouridine (H4Urd), surpasses the efficacy of 5-trifluorothymidine and 5-trifluoromethyl-2'-deoxycyti-dine when administered alone as demonstrated with adenocarcinoma 755 and Lewis lung carcinoma as solid tumors implanted in C57BL x DBA/2 Ft 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-β -D-arabinofurano-sylcytosine. 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 Famethyl-dCyd and its anabolites, compared to that of the commonly utilized fluorinated pyrimidines, indicate that F3methykJCyd + 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-fluorodeoxyuri-dine and to be essentially equal in efficacy to 5-fluorodeoxycyti-dine (+ 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 Fsmethyl-dCyd indicate that the major pathway of tumor inhibition is via conversion of F3methy IdCyd 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. The most efficacious coadministered doses of H4Urd (25 or 50 mg/kg) result in greater than 90% inhibition of the cytidine deaminase of serum, spleen, and liver and 65 and 55% inhibition of bone marrow and intestine, respectively; whereas, tumor cytidine deaminase is only moderately inhibited (33%). These findings relate to a new approach in the chemotherapy of cancer: tumor-specific activation coupled with protection of normal tissues by using modulating concentrations of an inhibitor of a converting (or activating) enzyme. This strategy magnifies the intrinsic differences in enzyme levels between normal and tumor tissue, thereby allowing heightened selectivity.
|Original language||English (US)|
|Number of pages||11|
|State||Published - Nov 1 1985|
ASJC Scopus subject areas
- Cancer Research