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)