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Enhancement by Tetrahydrouridine of 1-ß-D-Arabinofuranosylcytosine (Cytarabine) Oral Activity in L1210 Leukemic Mice¹

Cancer Research, The Upjohn Company, Kalamazoo, Michigan 49001

Cytarabine (ara-C) (1-ß-D-arabinofuranosylcytosine, Cytosar) is useful in the treatment of human leukemias. In experimental animals, p.o. doses required to elicit an antitumor effect are about 3 to 10 times those required when the agent is administered parenterally. In humans, parenteral administration is used exclusively. The current study shows that tetrahydrouridine [1-(ß-D-ribofuranosyl)-4-hydroxy-3,4,5,6-tetrahydropyrimidin-2-(1H)-one, THU] markedly enhances the therapeutic effect of ara-C administered p.o. in the treatment of L1210 leukemic mice. Therapeutic results obtained with p.o. combinations of THU and ara-C are comparable to, or exceed those achieved with, i.p. ara-C alone. THU has little effect on the activity of ara-C administered i.p. THU itself, at the doses studied, has no observable toxicity or intrinsic antitumor activity.

THU is an effective inhibitor in vitro and in vivo of the enzyme (pyrimidine nucleoside deaminase) which converts ara-C to 1-ß-D-arabinofuranosyluracil (an inactive species). Inhibition of this process by THU results in increased plasma levels of ara-C. Maximum plasma levels of ara-C after p.o. administration of ara-C-THU combinations, although only about 20% of those achieved after i.p. administration of ara-C, are 3 to 5 times higher than those observed after p.o. administration of ara-C alone. Furthermore, p.o. administration of the combination results in an increased ara-C plasma half-life as compared to that found with ara-C administered i.p.

¹ Work supported by Contract PH43-68-1023 with Chemotherapy, National Cancer Institute, NIH, Bethesda, Md. 20014.

Received 12/ 5/69. Accepted 4/10/70.

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