Abstract
Studies recently undertaken in our laboratory have demonstrated the increased efficacy of 5-fluorodeoxycytidine (FdCyd) and 5-trifluoromethyldeoxycytidine (F(,3)methyldCyd) when co-administered with modulated levels of tetrahydrouridine (H(,4)Urd) over 5-fluorouracil (5-FUra), 5-fluorodeoxyuridine (FdUrd) and 5-trifluorothymidine (F(,3)dThd) in a variety of animal tumor models.Initial metabolism studies utilizing FdCyd alone in log phase human laryngeal epidermoid carcinoma cells (HEp-2) revealed (i) incorporation of the prodrug into DNA, (ii) co-administered dH(,4)Urd permitted linear incorporation of FdCyd into DNA and FdCyd + H(,4)Urd or dH(,4)Urd resulted in 2- and 25-fold increases in DNA incorporation, respectively, in log phase HEp-2 cells with no detectable FdUrd incorporation. FdUrd alone resulted in high levels of FdUrd incorporation into HEp-2 DNA. FdCyd alone and FdUrd resulted in production and incorporation of high levels of fluorouridine monophosphate (FUMP) into cytoplasmic and nuclear RNA while the use of FdCyd + H(,4)Urd or dH(,4)Urd resulted in no detectable FUMP incorporation in cytoplasmic or nuclear RNA. Pool size analysis comparing FdCyd alone vs. FdUrd revealed a 66% elevation of FUMP pools using FdUrd in HEp-2 cells, while no detectable FUMP was formed utilizing FdCyd + H(,4)Urd or dH(,4)Urd at optimum levels. The thymidylate synthetase inhibitor fluorodeoxyuridine monophosphate (FdUMP) was also quantified. A 2.3-fold increase and 3.2-fold decrease was obtained using FdCyd + H(,4)Urd and dH(,4)Urd, respectively. FdUMP pools increased an average of 34% using FdCyd + H(,4)Urd vs. FdUrd alone in log phase HEp-2 cells. These cell culture studies revealed the co-administration of H(,4)Urd with FdCyd effectively directs the metabolism of FdCyd to form significantly higher levels of FdUMP than does FdUrd alone without the formation of generally toxic RNA level antimetabolites (i.e. FUra, FUMP, FUrd).Studies with mammary adenocarcinoma-755 in its ascitic form in BD2F(,1) (BDF(,1) x C57 black) mice, utilizing FdCyd and modulating levels of H(,4)Urd, selectively reduced toxic antimetabolite production more than 100-fold in normal tissue vs. tumors when compared to FdUrd. Appropriate levels of H(,4)Urd co-administered with FdCyd permitted high level production of all DNA and RNA directed antimetabolites in tumor (FdUrd, FdUMP, FUra, FUrd, and FUMP), whereas the levels of toxic antimetabolites were markedly lower in normal tissue. (Abstract shortened with permission of author.)