Protective, tumor-selective dual pathway activation of 5-fluoro-2'-deoxycytidine provided by tetrahydrouridine in mice bearing mammary adenocarcinoma-755

Abstract

Treatment of C57BL X DBA/2 F (hereafter called BD2F) mice bearing ascitic mammary adenocarcinoma-755 (ADC-755) with [3H]-5-fluoro-2'-deoxycytidine ([3H]FdCyd) plus tetrahydrouridine (H4Urd) resulted in antimetabolite pool sizes indicative of a tumor-selective, dual pathway metabolism of FdCyd via both cytidine deaminase and deoxycytidine kinase. In contrast to the high levels of all RNA- and DNA-level antimetabolites (as assayed by high performance liquid chromatography) derived from FdCyd found in tumor tissue, normal tissues (bone marrow, intestine, liver, and spleen) and serum metabolized FdCyd to only a small extent following FdCyd plus H4Urd treatment. RNA-level antimetabolite pools and 5-fluoro-2'-deoxyuridine (FdUrd) were generally 100-fold lower in normal than in tumor tissue, and 5-fluoro-2'-deoxyuridylate was 10- to 15-fold lower in normal than in tumor tissue. The use of [3H]FdUrd, on the other hand, resulted in the formation of higher levels (10- to 40-fold) of DNA- and RNA-level antimetabolites in normal tissue and lower levels (1/8) of 5-fluoro-2'-deoxyuridylate in tumor tissue. Both [3H]FdCyd plus H4Urd and [3H]FdUrd were utilized at their optimal drug doses. FdUrd- and FdCyd-derived metabolic products incorporated into the RNA and DNA of normal and tumor tissue of BD2F mice bearing ADC-755 were also examined. The drug combination [3H]FdCyd plus H4Urd resulted in the selective incorporation of antimetabolites into tumor RNA and DNA; only a very small extent of antimetabolites incorporated into normal tissue RNA and DNA. FdCyd was incorporated 5- to 10-fold greater in tumor than intestine, liver, or spleen following FdCyd plus H4Urd administration. FdCyd incorporation was 190-fold greater in tumor than in bone marrow. Mice bearing ADC-755 treated with [3H]-FdUrd resulted in only marginal selectivity in terms of antimetabolite incorporation in tumor tissue. Deoxycytidylate and cytidine deaminase enzyme assays have confirmed that H4Urd administration effectively inhibited normal cytidine deaminase activities, while only weakly inhibiting the elevated levels found in tumor tissue. Thymidine kinase, deoxycytidine kinase, deoxycytidylate deaminase, and cytidine deaminase have been shown previously to be significantly elevated in the mouse tumor model used; these enzymatic elevations are also characteristic of many human tumors. Treatment with FdCyd plus H4Urd resulted in 17 of 30 cures against ADC-755 compared to 4 of 20 and 0 of 20 for 5-fluorouracil and 5-fluoro-2'-deoxyuridine treatments, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)