Rational design of arabinosyl nucleosides as antitumor and antiviral agents.
The rational design of antitumor and antiviral agents must ultimately take advantage of biochemical differences between normal host cells and transformed cells. The initial experiments must be performed with subcellular or cellular model systems. For the studies with arabinosyl nucleosides we have chosen those enzyme systems, synthesizing DNA and RNA; being precursor analogues, the different arabinosyl nucleosides have been added in the triphosphate state to the different DNA- and RNA polymerase assays. 1-beta-D-Arabinofuranosylcytosine-5'-triphosphate has been found to inhibit the RNA-dependent DNA polymerases (isolated from oncogenic RNA viruses) 200-fold more sensitively than viral and cellular DNA-dependent DNA polymerases. Recent results, showing that RNA-leukemia-virus-related sequences are present in DNA of some human leukemia patients might support the assumption that the efficacy of this antimetabolite in the treatment of acute leukemia is due to its, at least relative selective inhibitory activity on reverse transcriptase. 9-beta-D-Arabinofuranosyladenine-5'-triphosphate is a strong inhibitor of cellular DNA polymerases with the cytological consequence of an inhibition of cell proliferation. The clinical benefit of the compound in treatment of tumors is dependent on their levels of adenosine deaminase. The triphosphate of this compound is a 100-fold more sensitive inhibitor of the herpesvirus DNA polymerase compared to the cellular replicative DNA polymerase. In addition the analogue, incorporated into herpesvirus DNA, acts as chain terminator. These effects are the biochemical basis for the highly selective antiherpesvirus activity of this antimetabolite. The anomer 9-alpha-D-arabinofuranosyladenine-5'-triphosphate only inhibits cellular replicative DNA polymerase and has no effect on herpesvirus DNA polymerase. Consequently this agent acts only cytostatically and not antivirally. Concerning 1-beta-D-arabinofuranosyluracil and 1-beta-D-arabinofuranosylthymine no pronounced antitumor or antiviral effect is known.
D000818:Animals; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D001089:Arabinose / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D003561:Cytarabine / Q000494:pharmacology / Q000627:therapeutic use; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D006564:Herpesviridae; D051379:Mice; D008954:Models, Biological; D019384:Nucleic Acid Synthesis Inhibitors; D009705:Nucleosides / Q000302:isolation & purification / Q000494:pharmacology*; D011817:Rabbits; D012107:Research Design; D014740:Vidarabine / Q000494:pharmacology / Q000627:therapeutic use; D014777:Virus Diseases / Q000188:drug therapy
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D019384:Nucleic Acid Synthesis Inhibitors; D009705:Nucleosides; D003561:Cytarabine; D001089:Arabinose; D012321:DNA-Directed RNA Polymerases; D014740:Vidarabine