Use of 5-trifluoromethyldeoxycytidine and tetrahydrouridine to circumvent catabolism and exploit high levels of cytidine deaminase in tumors to achieve DNA- and target-directed therapies.
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)
Mekras
J A
JA
Boothman
D A
DA
Greer
S B
SB
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000032:analysis* / Q000037:antagonists & inhibitors; D004247:DNA / Q000378:metabolism*; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000378:metabolism; D005260:Female; D005467:Floxuridine / Q000627:therapeutic use; D005472:Fluorouracil / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D009700:Nucleoside Deaminases / Q000032:analysis*; D013767:Tetrahydrouridine / Q000008:administration & dosage*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014271:Trifluridine / Q000378:metabolism / Q000627:therapeutic use; D014529:Uridine / Q000031:analogs & derivatives*
D005467:Floxuridine; D003841:Deoxycytidine; D013767:Tetrahydrouridine; C046940:5-trifluoromethyl-2'-deoxycytidine; D004247:DNA; D013940:Thymidylate Synthase; D009700:Nucleoside Deaminases; D003564:Cytidine Deaminase; D014271:Trifluridine; D005472:Fluorouracil; D014529:Uridine