Metabolic activation and antineoplastic-selective mechanism of action of two novel fluoropyrimidines

The coadministration of tetrahydrouridine (H4Urd) diverted the metabolism of 3H-5-fluoro-2'-deoxycytidine (FdCyd) in human epidermoid laryngeal carcinoma (HEp-2) cells through the deoxycytidine kinase-deoxycytidylate deaminase (dCK-dCMPD) pathway to the formation of 5-fluorodeoxyuridylate (FdUMP) without the incorporation of 5-fluorouridylate (FUMP) into RNA or the formation of RNA-level antimetabolite pools. Antimetabolite pool sizes, as assayed by HPLC, following treatment of BD2F1 mice bearing ascitic mammary adenocarcinoma-755 (ADC-755) or Lewis lung carcinoma (LLC) with 3H-FdCyd + H4 Urd resulted in pool sizes indicative of a tumor-selective, dual pathway metabolism of FdCyd via both the cytidine deaminase-deoxythymidine kinase (CD-dTK) and dCK-dCMPD pathways. In contrast to the high levels of all RNA- and DNA-level antimetabolites derived from FdCyd found in tumor tissue, in normal tissues (bone marrow, intestine, liver and spleen) and in serum, FdCyd was metabolized to only a small extent, all antimetabolite pools were markedly lower. 3H-FdCyd + H4Urd exposure resulted in selective incorporation of antimetabolites into tumor RNA and DNA. dCMPD and CD enzyme assays have confirmed that H4Urd administration effectively inhibited the low CD activity in normal, but not the elevated levels found in tumor tissue