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Metabolism and Selective Cytotoxicity of 9-ß-D-Arabinofuranosylguanine in Human Lymphoblasts¹

Departments of Internal Medicine [D. S. S., P. E. D., E. A., B. S. M.], and Biological Chemistry [P. E. D.], University of Michigan, Ann Arbor, Michigan 48109

The selective toxicity of purine deoxyribonucleosides for T-lymphoblasts appears to be mediated by the selective accumulation of the corresponding deoxyribonucleoside triphosphates in these cells. This finding has led to a search for deoxyribonucleoside analogues which may have clinical utility in T-cell lymphoproliferative disorders. 9-ß-D-arabinofuranosylguanine (ara-G) is a 2'-deoxyguanosine analogue which is 70-fold more inhibitory to the growth of T- than of B-lymphoblasts. It is less potent than ara-C but far more selective in its cytotoxic effect on T-cells. ara-G is not significantly degraded by purine nucleoside phosphorylase (EC 2.4.2.1) activity in T-lymphoblasts and is metabolized to 9-ß-D-arabinofuranosylguanine 5'-triphosphate. The accumulation of this metabolite directly correlates with inhibition of DNA but not of RNA or protein synthesis. MOLT-4 T-lymphoblasts were selected for ara-G resistance, and six clones were identified which exhibited a major degree of resistance to 2'-deoxyguanosine but little or none to ara-C. Further characterization of clone 24B3 revealed a 600-fold increase in ara-G resistance, a 36-fold increase in 2'-deoxyguanosine resistance, and only a 4-fold increase in 1-ß-D-arabinofuranosylcytosine resistance. The 24B3 cell line accumulated less than 10% of 9-ß-D-arabinofuranosylguanine 5'-triphosphate and 2'-deoxyguanosine 5'-triphosphate from the corresponding nucleosides as compared to wild-type MOLT-4 cells; in contrast, 1-ß-D-arabinofuranosylcytosine 5'-triphosphate accumulation was approximately 30% of control values. Thus, ara-G differs from 1-ß-D-arabinofuranosylcytosine in its selectivity for cultured T-lymphoblasts and may be of use as a chemotherapeutic or immunosuppressive agent.

¹ This investigation was supported by Grants CA 34085 and CA 26284 awarded by the National Cancer Institute, Department of Health and Human Services, and Grant AM 19045 from NIH.

² Arthritis Foundation Fellow.

³ Scholar of the Leukemia Society of America. To whom requests for reprints should be addressed, at Simpson Memorial Institute, 102 Observatory, Ann Arbor, MI 48109.

Received 8/22/84. Accepted 12/ 4/84.

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