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Comparison of the Actions of 9-ß-D-Arabinofuranosyl-2-fluoroadenine and 9-ß-D-Arabinofuranosyladenine on Target Enzymes from Mouse Tumor Cells¹

Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama 35255

9-ß-D-Arabinofuranosyl-2-fluoroadenine (2-Fara-A), a derivative of 9-ß-D-arabinofuranosyladenine (ara-A) that is resistant to deamination, selectively inhibits DNA synthesis and has activity against mouse leukemia L1210 comparable to that of ara-A plus the adenosine deaminase inhibitor, 2'-deoxycoformycin. To determine if these two nucleosides have similar modes of action, comparisons were made of their effects and those of their triphosphates on enzymes known to be inhibited by ara-A or 9-ß-D-arabinofuranosyladenine 5'-triphosphate. 9-ß-D-Arabinofuranosyl-2-fluoroadenine 5'-triphosphate was more effective than 9-ß-D-arabinofuranosyladenine 5'-triphosphate in inhibiting the reduction of adenosine 5'-diphosphate and cytidine 5'-diphosphate by ribonucleotide reductase from HEp-2 cells or L1210 cells. DNA polymerase from L1210 cells was equally sensitive to 9-ß-D-arabinofuranosyl-2-fluoroadenine 5'-triphosphate and 9-ß-D-arabinofuranosyladenine 5'-triphosphate, and DNA polymerase ß from L1210 cells was much less sensitive to both triphosphates. S-Adenosylhomocysteine hydrolase from L1210 cells was inactivated by 2-F-ara-A and ara-A, but higher concentrations of the fluoro derivative were required. These results are consistent with 2-F-ara-A and ara-A inhibition of DNA synthesis by inhibition of ribonucleotide reductase and DNA polymerase .

¹ This work was supported by USPHS Grant CA-23155, awarded by the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed, at Kettering-Meyer Laboratory, Southern Research Institute, 2000 Ninth Avenue South, P. O. Box 3307-A, Birmingham, Ala. 35255.

Received 11/13/81. Accepted 3/12/82.

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