The metabolic products formed and incorporated into the
nucleic acids (
RNA and
DNA) of mice bearing
Lewis lung carcinoma (LLC) following optimal doses of
5-fluorouracil (FUra),
5-fluoro-2'-deoxyuridine (FdUrd), and
5-fluoro-2'-deoxycytidine (FdCyd) coadministered with
tetrahydrouridine (H4Urd), a potent inhibitor of
cytidine deaminase, were examined. Treatment with FdCyd plus H4Urd resulted in a
tumor-selective incorporation and formation of
antimetabolites compared to either FUra or FdUrd treatments. Between 45- and greater than 5400-fold higher levels of the potent
thymidylate synthetase inhibitor, 5-fluoro-2'-deoxyuridylate (
FdUMP), were formed in
tumor than in any of the normal tissues analyzed.
RNA-level
antimetabolites (FUra, 5-fluorouridine, and 5-fluorouridylate) were also between 3 and greater than 990-fold higher in
tumor compared to normal tissue following FdCyd plus H4Urd administration.
DNA-level
antimetabolites (FdCyd, 5-fluorodeoxycytidylate, FdUrd, and
FdUMP) were from 2- to 6-fold higher in
tumor compared to normal tissue. FUra and FdUrd treatments resulted in between 3 and greater than 1300-fold higher
RNA-level
antimetabolites and from 4 to greater than 1020-fold higher
FdUMP pools in normal tissues than FdCyd plus H4Urd treatment.
DNA-level
antimetabolites were also from 4- to 32-fold higher in normal tissues following optimal doses of FUra or FdUrd. In
tumor tissue, optimal doses of FUra or FdUrd resulted in lower (a)
FdUMP levels (5- to 2-fold), (b)
RNA-level
antimetabolites (6- to 3-fold), and (c)
DNA-level
antimetabolites (10- to 4-fold) compared to an optimal dosage of FdCyd plus H4Urd. In serum, the administration of H4Urd resulted in the protection of FdCyd from systemic catabolism, unlike that found with FUra or FdUrd. Substantial levels of
FdUMP, FUrd, and FUMP were noted in serum following FUra or FdUrd treatment. The formation of di- and
triphosphate antimetabolite pools and the incorporation of
antimetabolites into the
RNA and
DNA of normal and
tumor tissues demonstrated trends similar to those mentioned above with
nucleoside, mononucleotide, and free base pools. H4Urd treatment of 25 mg/kg did not affect the elevated levels of
deoxycytidine kinase or
deoxycytidylate deaminase in LLC
tumor tissue or the low levels found in normal tissue. A critical feature of this chemotherapeutic strategy using FdCyd plus H4Urd was that the elevated level of
cytidine deaminase in LLC
tumor tissue was inhibited less than 10% by the administration of 25 mg/kg H4Urd, whereas
deoxycytidine deaminase activities in normal tissues (including bone marrow and intestine) were inhibited greater than 93%.(ABSTRACT TRUNCATED AT 400 WORDS)