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Comparison of the Toxicity and Metabolism of 9-ß-D-Arabinofuranosyl-2-fluoroadenine and 9-ß-D-Arabinofuranosyladenine in Human Lymphoblastoid Cells¹

Department of Developmental Therapeutics, The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77030 [W. P., S. C., L. A.], and Organic Chemistry Department, Southern Research Institute, Birmingham, Alabama 35205 [J. A. M.]

The toxicity and metabolism of 9-ß-D-arabinofuranosyl-2-fluoroadenine (F-ara-A), an adenosine deaminase-resistant nucleoside analog, have been compared to those of 9-ß-D-arabinofuranosyladenine (ara-A) in the presence of the adenosine deaminase inhibitor, deoxycoformycin. Equal concentrations of F-ara-A and ara-A plus deoxycoformycin produced similar inhibition of growth of CCRF-CEM human lymphoblastoid cells. 9-ß-D-Arabinofuranosyl-2-fluoroadenine 5'-triphosphate (F-ara-ATP) and 9-ß-D-arabinofuranosyladenine 5'-triphosphate (ara-ATP), were concentratively accumulated intracellularly and exerted their major inhibitory effect on DNA synthesis. Two approaches were used to compare the effect of these nucleotide analogs on the DNA-synthetic capacity of whole cells. (a) The concentrations of F-ara-ATP and ara-ATP in cells incubated with the respective nucleosides were determined directly at the same time that the DNA-synthetic capacity of the cells in each culture was measured by incorporation of [³H]thymidine into DNA. Neither compound significantly affected the specific activity of cellular [³H]deoxythymidine triphosphate. (b) The rates of disappearance of F-ara-ATP and ara-ATP from cells washed free of the nucleosides were determined. These values were used to calculate the cellular concentration of each nucleotide analog in cells in which DNA-synthetic capacity was monitored after incubation with F-ara-A or ara-A plus deoxycoformycin and washed into fresh media. These determinations indicated that the rates of accumulation of F-ara-ATP and ara-ATP differed and were related to the concentration of the exogenous nucleoside. F-ara-ATP disappeared from cells in drug-free media at several times the rate of the disappearance of ara-ATP. However, at equal cellular concentrations, F-ara-ATP was slightly more inhibitory to the processes measured by thymidine incorporation than was ara-ATP. We conclude that F-ara-ATP and ara-ATP share a similar mechanism of action and potency of inhibition of DNA synthesis. The fact that F-ara-A retains its cytotoxic efficacy in the absence of inhibitors of adenosine deaminase provides a rationale for investigating its antitumor properties further.

¹ Supported by NIH Grants CA 14528, CA 11520, and RR 05511; Contract N01 CM 87185; and American Cancer Society Grant CH-130.

² To whom requests for reprints should be addressed.

Received 11/15/79. Accepted 4/ 3/80.

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