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Tumor-selective Metabolism of 5-Fluoro-2'-deoxycytidine Coadministered with Tetrahydrouridine Compared to 5-Fluorouracil in Mice Bearing Lewis Lung Carcinoma¹

Departments of Microbiology and Immunology [D. A. B., S. G.], Oncology and Biochemistry [S. G.], and Biochemistry, Epidemiology, and Public Health [T. V. B.], School of Medicine, University of Miami, Miami, Florida 33101

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'-deoxyuridine (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 >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 >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 >1300-fold higher RNA-level antimetabolites and from 4 to >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 <10% by the administration of 25 mg/kg H₄Urd, whereas deoxycytidine deaminase activities in normal tissues (including bone marrow and intestine) were inhibited >93%. Although [³H]FdCyd was utilized far more by cytidine deaminase (2.8- to 7.8-fold), deoxycytidylate deaminase (3.3- to 13.7-fold), and deoxycytidine kinase (1.6- to 6.7-fold) than [³H]deoxycytidine in various normal and tumor tissues, H₄Urd administration resulted in similar inhibitory effects. The tumor-selective synergistic action of all the formed and incorporated antimetabolites observed following FdCyd plus H₄Urd treatment may well explain the far superior antitumor efficacy observed compared to those of FdUrd and FUra against LLC.

¹ This research was supported, in part, by Grant CA33219 from the National Cancer Institute as well as the Women's Cancer Association of the University of Miami and gifts from the private sector including Readmore Publications and the Weeks Foundation. The work presented in this paper is derived from the Ph.D. dissertation of David A. Boothman, University of Miami, January 1986. This paper is dedicated to the memory of Dr. Francis J. Ryan (1916 to 1963), who served as mentor to Dr. Sheldon Greer at Columbia University, New York, NY.

² Present address: Division of Cell Growth and Regulation (D-810A), Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA 02115.

³ To whom requests for reprints should be addressed.

Received 5/23/86. Revised 10/29/86. Revised 1/27/87. Accepted 2/ 5/87.

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