Abstract
Treatment of C57BL × DBA/2 F1 (hereafter called BD2F1) 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]FdUrd 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 BD2F1 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. FdCyd plus H4Urd has been shown to be more efficacious than FdUrd or 5-fluorouracil used at their optimal drug doses against solid and ascitic ADC-755 and against Lewis lung carcinoma in its solid form (Cancer Res., 44: 2551–2560, 1984).
This 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 Oncology 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.
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