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Biochemical and Antitumor Effects of the Combination of Thymidine and 1-ß-D-Arabinofuranosylcytosine against Leukemia L1210¹

Department of Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Memorial Institute, Buffalo, New York 14263

Exposure of L1210 cells in culture to 5.6, 60, 150, and 350 µM thymidine (dThd) led to 0, 33, 50, and 71% inhibition of their rates of steady-state growth. Following treatment with 0.04 µM 1-ß-D-arabinofuranosylcytosine (ara-C), this dThd treatment produced an increase in the apparent rates of 1-ß-D-arabinosylcytosine triphosphate (ara-CTP) incorporation into nucleic acids amounting to 6-, 36-, 48-, and 60-fold, respectively, that observed in control cells. Equivalentfold increases in the corresponding intracellular concentrations of ara-CTP also occurred. At higher ara-C concentrations (to 3.0 µM), the enhancement of analog incorporation in dThd-treated cells relative to control cells was greatly reduced (to 2- to 4-fold). In addition, the dThd-induced increase in the concentration of ara-CTP did not parallel the increase in apparent rate of ara-CTP incorporation into nucleic acid at the higher concentrations of ara-C. Addition of deoxycytidine and cytidine to the medium prevented both the growth inhibition and the enhanced ara-CTP incorporation observed in the presence of dThd. Pretreatment of L1210 cells with 150 µM dThd for 24 hr before their exposure to dThd and ara-C resulted in a one-log increase in cytotoxicity, relative to the effects of ara-C alone in previously untreated cells. These cell culture observations prompted an evaluation of the chemotherapeutic potential of this combination in mice bearing leukemia L1210. dThd concentrations comparable to those inhibiting the growth rate of L1210 cells in culture by 50% were achieved and maintained in mouse plasma by the continuous i.v. infusion of dThd at 5 g/kg/day. Alternating 24-hr infusion of this dose of dThd with 24-hr infusion of ara-C at 2, 4, or 8 mg/kg/day for a total of 6 days increased the mean survival of mice bearing leukemia L1210 by 35, 203 (plus 33% long-term survivors), and 19% relative to untreated mice. Simultaneous continuous infusion of optimal doses of dThd (5 g/kg/day) and ara-C (2 mg/kg/day) for 5 days resulted in an increased life span of 101% as compared to an 87% increased life span obtained with ara-C alone. The administration of dThd at either less than or greater than the optimal dose simultaneous with ara-C resulted in survival well below that obtained with ara-C alone. These results suggest that the efficacy of simultaneous continuous infusion of dThd and ara-C is only slightly greater than that of the continuous infusion of ara-C alone. However, pretreatment by dThd followed by ara-C is superior to that achieved with the optimal schedule of ara-C alone against this murine leukemia.

¹ This investigation was supported by USPHS Research Grant CA-17156 from the National Cancer Institute.

² Present address: Division of Oncology, New York Medical College, Valhalla, N. Y. 10595.

³ Recipient of National Research Service Award CA-09072 from the National Cancer Institute. To whom requests for reprints should be addressed, at Grace Cancer Drug Center, Roswell Park Memorial Institute, 666 Elm St., Buffalo, N. Y. 14263.

⁴ Present address: Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Ind. 46206.

Received 5/ 5/80. Accepted 10/20/80.