The lethality of aranucleotides.
Certain D-arabinosyl nucleosides, notably D-arabinosyl cytosine (araC) and D-arabinosyl adenine (araA), are useful in the treatment of certain leukemias and some DNA virus infections, respectively. The compounds are lethal to animal cells and some bacteria. Despite extensive deamination, the parent nucleosides are transported within sensitive cells and phosphorylated to the mono-, di- and triphosphates. AraCTP and araATP are good specific competitive inhibitors of tumor cell or virus-induced DNA polymerases, competing with dCTP and dATP, respectively. In addition to markedly inhibiting DNA synthesis, the aranucleotides enter newly formed DNA in internucleotide linkage. Sensitivity to the nucleosides appears to correlate with the relative ratio of formation of the triphosphate via a nucleoside kinase to degradation of the nucleoside via a nucleoside deaminase. Inhibition of the deaminase increases formation of the aranucleoside triphosphate in leukemic or virus-infected cells and markedly increases the toxicity of the nucleosides. Combinations of inhibitors of the deaminases and of the arnaucleoside are being explored in clinical situations. In addition, the slow penetration of aranucleotides into cells has been observed and some of these 5'-phosphates are useful antiviral agents, e.g. against herpes virus in herpetic keratitis.
D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D003561:Cytarabine / Q000378:metabolism / Q000633:toxicity*; D004247:DNA / Q000096:biosynthesis; D004261:DNA Replication / Q000187:drug effects; D004279:DNA, Viral / Q000096:biosynthesis; D004285:Dogs; D000882:Haplorhini; D051379:Mice; D012377:Rodentia; D014740:Vidarabine / Q000378:metabolism / Q000633:toxicity*; D014779:Virus Replication / Q000187:drug effects
D004279:DNA, Viral; D003561:Cytarabine; D004247:DNA; D014740:Vidarabine