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Antitumor Activity and Biochemical Effects of Cyclopentenyl Cytosine in Mice

Laboratory of Biological Chemistry [J. D. M., N. M. M.] and Laboratory of Pharmacology and Experimental Therapeutics [S. P. T., V. E. M.], Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20892

Cyclopentenyl cytosine, a recently synthesized inhibitor of cytidine 5'-triphosphate synthesis, has marked antitumor activity. Treatment with 1 mg/kg i.p. on days 1–9 following inoculation with tumor produced 111–122% increased median life span in mice bearing L1210 leukemia, 73–129% increased median life span in mice bearing P388 leukemia, and 58–62% increased median life span in mice with B16 melanoma. A subline of L1210 selected for resistance to 1-ß-D-arabinofuranosylcytosine was more sensitive to cyclopentenyl cytosine than the parent tumor line. L1210 cell growth in cultures was greatly inhibited (>90%) by 0.1 µM cyclopentenyl cytosine, but cells were protected from the growth inhibitory effects by cytidine (20 µM) and to a lesser extent by uridine or deoxycytidine. Exposure of cultured L1210 cells to 1 µM cyclopentenyl cytosine inhibited formation of [³H]cytidine nucleotides from [³H]uridine by 30% during the first 15 min of exposure to drug and by >95% after 2 h of exposure. Treatment of mice bearing L1210 ascites with cyclopentenyl cytosine (1 mg/kg) produced rapid depletion of cytidine nucleotide pools in the tumor cells; these pools fell to 35% of control within 30 min. The effects of cyclopentenyl cytosine on nucleotide pools were tissue selective; the cytidine nucleotide pools of spleen, liver, kidney, and intestine were less sensitive than that of the L1210 ascites tumor. Cytidine nucleotide pools of spleen and liver were depleted by higher doses (10 mg/kg) of cyclopentenyl cytosine.

¹ To whom requests for reprints should be addressed.

Received 10/ 8/85. Revised 2/18/86. Accepted 3/24/86.

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