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Correlation of Cytotoxicity with Total Intracellular Exposure to 9-ß-D-Arabinofuranosyladenine 5'-Triphosphate¹

The Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, and the Department of Developmental Therapeutics, The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77030

The mechanism by which 9-ß-D-arabinofuranosyladenine produces cell death has been studied extensively, but the details remain controversial. The results presented here describe an evaluation of 9-ß-D-arabinofuranosyladenine-induced cytotoxicity in terms of the product of the total amount of the active 5'-triphosphate metabolite, 9-ß-D-arabinofuranosyladenine 5'-triphosphate (ara-ATP), which accumulated in the cells, and the duration of the exposure expressed in units of ara-ATP µM-hr. It was demonstrated that a strong correlation exists between these parameters which was not affected by the rat of accumulation of ara-ATP. In addition, inhibition of 9-ß-D-arabinofuranosyladenine deamination by 2'-deoxycoformycin did not alter the relationship between cell death and total intracellular exposure to ara-ATP. The consistency of this relationship both within and between experiments indicates that the quantitation of the total cellular exposure to ara-ATP is useful in predicting cytotoxicity.

¹ This work was supported in part by NIH Grants CA 14528 and CA 28596, and by Grant CH-130A from the American Cancer Society.

² Recipient of a Rosalie B. Hite Predoctoral Fellowship. Present address: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Mich. 48109.

³ To whom requests for reprints should be addressed.

Received 1/26/82. Accepted 6/15/82.

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