The 2-fluoro derivative of 9-β-d-arabinofuranosyladenine (2-F-ara-A) and its soluble 5′-formate and 5′-phosphate derivatives were therapeutically effective against the parent leukemia L1210 (L1210/0). 2-F-ara-A and 9-β-d-arabinofuranosyladenine 5′-formate were inactive against a 1-β-d-arabinofuranosylcytosine-resistant subline (L1210/ara-C) that was deficient in deoxycytidine kinase. Deoxycytidine prevented 2-F-ara-A-induced inhibition of proliferation of L1210/0 cells in culture and alleviated 2-F-ara-A inhibition of DNA synthesis.

After treatment of mice with 9-β-d-arabinofuranosyladenine 5′-formate, intracellular levels of the 5′-triphosphate of 9-β-d-arabinofuranosylfluoroadenine in leukemia cells were more than 10 times higher in L1210/0 cells than in L1210/ara-C cells. Similar results were obtained in this line of leukemia cells from mice treated with the 5′-monophosphate of 9-β-d-arabinofuranosyl-2-fluoroadenine. Thus, L1210/ara-C cells deficient in deoxycytidine kinase activity were also deficient in capacity to phosphorylate 2-F-ara-A.

Kinase activity from L1210/0 cells for deoxycytidine and for 2-F-ara-A coeluted from calcium phosphate cellulose and from diethylaminoethyl cellulose columns and had similar mobility on gel electrophoresis. Deoxyadenosine kinase was clearly separated from deoxycytidine kinase. Deoxycytidine competed with 2-F-ara-A for phosphorylation by the partially purified enzyme from L1210 cells. These results indicate that 2-F-ara-A is phosphorylated to the 5′-monophosphate by deoxycytidine kinase of leukemia L1210 cells.

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These studies were supported by Grants CA-23155 and CA-27448 and by Contracts NO1-CM-43756 and NO1-CM-43762, Division of Cancer Treatment, National Cancer Institute, NIH, and the Department of Health, Education, and Welfare.

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