title: The mechanisms of lethal action of arabinosyl cytosine (araC) and arabinosyl adenine (araA).
abstract: Certain D-arabinosyl nucleosides, notably arabinosyl cytosine (araC) and 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 of 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 aranucleoside 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 kiratitis.
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D058892:Adenosine Deaminase Inhibitors; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003561:Cytarabine / Q000378:metabolism / Q000494:pharmacology*; D003564:Cytidine Deaminase / Q000378:metabolism; D003597:Cytosine Nucleotides / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D003853:Deoxyribonucleosides / Q000494:pharmacology; D006801:Humans; D007292:Inosine Nucleotides / Q000378:metabolism; D007938:Leukemia / Q000188:drug therapy; D013767:Tetrahydrouridine / Q000494:pharmacology; D014740:Vidarabine / Q000378:metabolism / Q000494:pharmacology*; D014777:Virus Diseases / Q000188:drug therapy
chemical_list: D058892:Adenosine Deaminase Inhibitors; D001381:Azepines; D003597:Cytosine Nucleotides; D003853:Deoxyribonucleosides; D007292:Inosine Nucleotides; D003561:Cytarabine; D013767:Tetrahydrouridine; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D004247:DNA; D003564:Cytidine Deaminase; D014740:Vidarabine; D000225:Adenine