Mice Bearing Mammary Adenocarcinoma-755-deoxycytidine Provided by Tetrahydrouridine in ′ 5-Fluoro-2 Protective , Tumor-selective Dual Pathway Activation of Updated Version

Treatment of C57BL x DBA/2 F, (hereafter called BD2F,) mice bearing ascitic mammary adenocarcinoma-755 (AIM'-755) with |'H|-5fluoro-2'-deoxycytidine (|3H]FdCyd) plus tetrahydrouridine (H<Urd) re sulted 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 RNAand 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 114I rd 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 10to 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 (10to 40-fold) of DNAand RNA-level antimetabolites in normal tissue and lower levels (1/8) of S-fluoro-2'-deoxyuridylate in tumor tissue. Both [3H]FdCyd plus IU 'rd and | 'H|I dlrd were utilized at their optimal drug doses. FdUrdand FdCyd-derived metabolic products incorporated into the RNA and DNA of normal and tumor tissue of BD2I, mice bearing AIM 755 were also examined. The drug combination [3H]FdCyd plus I I4l'rd 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 5to 10-fold greater in tumor than intestine, liver, or spleen following FdCyd plus IU rd administration. FdCyd incorporation was 190-fold greater in tumor than in bone marrow. Mice bearing AIM -755 treated with f 11|FdUrd resulted in only marginal selectivity in terms of antimetabolite incorporation in tumor tissue. Deoxycytidylate and cytidine deaminase enzyme assays have confirmed that I I4l rd administration effectively inhibited normal cytidine deami nase 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 IM 'rd resulted in 17 of 30 cures against ADC-755 compared to 4 of 20 and 0 of 20 for 5-fluorouracil and 5-fluoro2'-deoxyuridine treatments, respectively. FdCyd plus H4Urd has been shown to be more efficacious than FdUrd or 5-fluorouracil used at their Received 8/6/85; revised 5/27/86, 8/15/86, 1/27/87; accepted 2/5/87. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1This research was supported in part by Grant CA 33219 from the National Cancer Institute, the Women's Cancer Association of the University of Miami, and gifts from the private sector, including Readmore Publications and the Weeks Foundation. A preliminary account of this work was presented at the joint American Association for Cancer Research/American Society of Clinical Oncol ogy annual meeting held in Houston, Texas, May 22-25, 1985. This and the second paper entitled, "Tumor-Selective Metabolism of 5-Fluoro-2'-deoxycytidine Coadministered with Tetrahydrouridine Compared To 5-Fluorouracil in Mice Bearing Lewis Lung Carcinoma," by D. A. Boothman, T. V. Briggle, and S. Greer, are dedicated to Frances and Raymond Boothman. 1 Present address: Department of Pharmacology, Harvard Medical School and Division of Cell Growth and Regulation (D-81OA), Dana-Farber Cancer Institute, Boston, MA 02II5. 1To whom requests for reprints should be addressed. optimal drug doses against solid and ascitic ADC-755 and against Lewis lung carcinoma in its solid form (Cancer Res., 44: 2551-2560,1984).