The selectivity of action of 1-β-d-arabinofuranosylcytosine (ara-C) against leukemic cells was studied in vivo. Dynamic state tissue levels of ara-C and of its mono-, di-, and triphosphate (ara-CTP) were measured in L1210 leukemic cells and in C57BL × DBA/2 F1 host tissues at different times after various doses of the agent. The levels were correlated with inhibition of of thymidine incorporation into DNA and with cytocidal effects as measured by loss of isotopically prelabeled DNA. ara-CTP levels, but not those of the mono- and diphosphates of ara-C, were higher in leukemic cells and in host cell renewal systems than in other host tissues. DNA synthesis was equally inhibited by similar levels of ara-CTP in ascitic L1210 cells, in leukemic infiltrates in liver, and in small intestine. However, L1210 cells accumulated higher levels of ara-CTP for longer periods than did small intestine, and correspondingly the inhibition of DNA synthesis was greater and more prolonged in leukemic cells. ara-C caused greater losses of prelabeled DNA in ascites cells and in infiltrated liver than in host small intestine. It appears that the differential net tissue level of ara-CTP and its duration are the determinants of chemotherapeutic efficacy of ara-C against L1210 leukemia.

ara-C was the predominant nucleoside present in hydrolysates of ara-CTP fractions. By contrast, 1-β-d-arabinofuranosyluracil predominated in hydrolysates of monophosphate nucleotide fractions from ascites cells, liver, small intestine, and blood. Monophosphate nucleotide was also present in ascites fluid and plasma.

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This work was supported in part by National Cancer Institute Grant CA-08748 and by the Elsa U. Pardee Foundation. Part of this study was presented at the 27th Annual Symposium on Fundamental Cancer Research, Houston, Texas, February 1974, and at the 65th Annual Meeting of the American Association for Cancer Research, Houston, Texas, March 1974.

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