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Metabolism of 1-ß-D-Arabinofuranosyl-5-azacytosine and Incorporation into DNA of Human T-Lymphoblastic Cells (Molt-4)¹

Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514 [A. T., J-M. L., G. D., Y-c. C.], and Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20205 [D.C.]

1-ß-D-Arabinofuranosyl-5-azacytosine (ara-5-aza-Cyd) had potent cytotoxicity against human T-type lymphoblastic cells in culture. When Molt-4 cells were exposed to ara-5-aza-Cyd for 24 h, clonogenic survival was reduced by 50 and 98% at initial concentrations of 10^-7 and 10^-6 M, respectively, compared to 3 x 10^-8 and 10^-6 M, respectively, for the same effect with 1-ß-D-arabinofuranosylcytosine (ara-C). The analogue is chemically unstable, with a t of 12 h at 37°C in phosphate-buffered saline. ara-5-aza-Cyd is not significantly deaminated by human Cyddeoxycytidine (dCyd) deaminase, in contrast to ara-C. It is phosphorylated by human cytoplasmic dCyd kinase, with a K_m of 55 µM and a relative V_max of 310% compared to dCyd. The primary metabolite (70%) in Molt-4 cells was identified as ara-5-aza-Cyd triphosphate. Thymidine but not uridine or amino acid incorporation was inhibited by ara-5-aza-Cyd. ara-5-aza-Cyd was incorporated in a dose-dependent manner into DNA, but not RNA, primarily in internucleotide linkage as the original compound. Incorporation into the cellular methanol-insoluble fraction was 3- to 5-fold higher at 8 h than was ara-C incorporation. ara-5-aza-Cyd may have a unique activity against tumor cells resistant to ara-C, particularly where high Cyd-dCyd deaminase activity is a factor. The mode of action, like that of ara-C, is probably mediated through its incorporation into DNA and inhibition of DNA synthesis.

¹ This research was supported in part by Grant CA-27448 from the National Cancer Institute.

² To whom requests for reprints should be addressed.

Received 1/10/85. Revised 4/24/85. Accepted 4/26/85.

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