Comparison of the actions of 9-beta-D-arabinofuranosyl-2-fluoroadenine and 9-beta-D-arabinofuranosyladenine on target enzymes from mouse tumor cells.
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 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-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, and 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.
D043383:Adenosylhomocysteinase; D000818:Animals; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors; D004261:DNA Replication / Q000187:drug effects*; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D007939:Leukemia L1210 / Q000201:enzymology*; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology*
D019384:Nucleic Acid Synthesis Inhibitors; D012264:Ribonucleotide Reductases; D004256:DNA Polymerase I; D004257:DNA Polymerase II; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D014740:Vidarabine; C024352:fludarabine