COMPARISON OF THE ACTIONS OF 9-BETA-D-ARABINOFURANOSYL-2-FLUOROADENINE AND 9-BETA-D-ARABINOFURANOSYLADENINE ON TARGET ENZYMES FROM MOUSE-TUMOR CELLS

  • 1 January 1982
    • journal article
    • research article
    • Vol. 42  (6) , 2260-2264
Abstract
9-.beta.-D-Arabinofuranosyl-2-fluoroadenine (2-F-ara-A), a derivative of 9-.beta.-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 2 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-.beta.-D-arabinofuranosyladenine 5''-triphosphate. 9-.beta.-D-Arabinofuranosyl-2-fluoroadenine 5''-triphosphate was more effective than 9-.beta.-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 .alpha. from L1210 cells was equally sensitive to 9-.beta.-D-arabinofuranosyl-2-fluoroadenine 5''-triphosphate and 9-.beta.-D-arabinofuranosyladenine 5''-triphosphate; DNA polymerase .beta. 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 .alpha.