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Differences in Metabolism and Cytotoxicity between 9-ß-D-Arabinofuranosyladenine and 9-ß-D-Arabinofuranosyl-2-fluoroadenine in Human Leukemic Lymphoblasts¹

Divisions of Biochemical and Clinical Pharmacology [A. F., D. E. B.] and Hematology-Oncology [L. W. D., L. P.], St. Jude Children's Research Hospital, Memphis, Tennessee 38101

We compared the effects of 9-ß-D-arabinofuranosyladenine (ara-A) and its 2-fluoro derivative (F-ara-A) on DNA synthesis and viability in human leukemic lymphoblasts (CCRF-CEM). The relative DNA content and cloning capacity of the cells were determined by flow cytometry and growth in methylcellulose, respectively. Incubation with either 1 µM ara-A in the presence of 2'-deoxycoformycin, a potent inhibitor of adenosine deaminase, or 2.5 µM F-ara-A alone for 18 hr stopped the progression of cells through S phase. At higher concentrations, from 2.5 to 20 µM, both arabinonucleosides preferentially produced toxic effects in cells arrested in S phase. The DNA-inhibitory effects and cytotoxicity of F-ara-A, but not ara-A, were prevented by adding deoxycytidine to the growth medium. A CCRF-CEM variant that was unable to phosphorylate deoxycytidine proved to be highly resistant to the inhibitory effects of F-ara-A but was normally sensitive to ara-A. These results indicate that the cytotoxicity of ara-A in both sensitive and resistant cells and of F-ara-A in sensitive cells is probably mediated by the intracellular formation of nucleotides and inhibition of DNA synthesis. By contrast, the reduction in the cloning efficiency of 1-ß-D-arabinofuranosylcytosine-resistant cells at high concentrations of F-ara-A may be due to some direct effect of the nucleoside. Finally, the different susceptibility of the mutant CCRF-CEM cells to the toxic effects of ara-A and F-ara-A suggests that alternative pathways phosphorylate these arabinonucleosides, one being associated with deoxycytidine kinase and the other with either deoxyadenosine kinase or, less likely, adenosine kinase.

¹ Supported by Research Project Grant CH-52A from the American Cancer Society, Research Project Grant CA-18446, Leukemia Program Project Grant CA-20180, Cancer Center Support (CORE) Grant CA-21764 from the National Cancer Institute, and American Lebanese Syrian Associated Charities (ALSAC).

² To whom requests for reprints should be addressed, at St. Jude Children's Research Hospital, 332 N. Lauderdale, P. O. Box 318, Memphis, Tenn. 38101.

Received 8/31/79. Accepted 1/29/80.

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