Mode of action of 9-beta-D-arabinofuranosyladenine on the synthesis of DNA, RNA, and protein in vivo and in vitro.
The influence of 9-beta-D-arabinofuranosyladenine (ara-A) and its 5'-triphosphate derivative on programmed synthesis was tested with an intact cell system as well as with isolated enzyme systems. The effect of ara-A was tested in mouse lymphoma cells (L5178Y). The compound reduces cell proliferation in low concentration by cytostasis; under high ara-A concentration of radioactive precursors into DNA, RNA, and protein showed that ara-A selectively inhibits DNA synthesis. Formation of a polysome complex is not affected by ara-A. [3H]ara-A is incorporated into DNA in an intact cell system; 1 molecule of ara-A is incorporated per 8000 molecules of deoxyadenosine. Most of the ara-A molecules appeared to be in internucleotide linkages. Incorporation of ara-A into RNA could not be detected. 9-BETA-D-Arabinofuranosyladenine 5'-triphosphate (ara-ATP) does not reduce the incorporation rate of the following enzymes, isolated from quail oviducts: DNA-dependent RNA polymerases I and II, polyadenylic acid polymerase, and poly(adenosine diphosphate ribose) polymerase. The compound was found to inhibit DNA synthesis catalyzed by DNA polymerases isolated from quail oviducts and from oncogenic RNA viruses (Rous sarcoma viruses). All the enzymes tested were inhibited by ara-ATP in a competitive way with respect to deoxyadenosine 5'-triphosphate. The highest affinity of ara-ATP, i.e., the highest inhibitory potency of the drug, was found in the assays with the eukaryotic low-molecular DNA-dependent DNA polymerase. The influence on the eukaryotic high-molecular DNA-dependent Dna polymerase was a litte less. Compared to the eukaryotic DNA polymerases, the viral enzymes (RNA-directed DNA polymerase and DNA-directed DNA polymerase) are affected to a smaller extent by ara-ATP. No effects of ara-A and ara-ATP are observed in a protein-synthesizing, cell-free system isolated from L5178Y cells.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002474:Cell-Free System; D004247:DNA / Q000032:analysis; D004254:DNA Nucleotidyltransferases / Q000037:antagonists & inhibitors; D004261:DNA Replication / Q000187:drug effects*; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D003864:Depression, Chemical; D005260:Female; D008223:Lymphoma; D008239:Lysine / Q000378:metabolism; D008970:Molecular Weight; D011062:Polynucleotide Adenylyltransferase / Q000378:metabolism; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D011684:Purine Nucleosides / Q000494:pharmacology*; D011784:Quail; D012313:RNA / Q000032:analysis; D013936:Thymidine / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014529:Uridine / Q000378:metabolism; D014740:Vidarabine / Q000494:pharmacology*
D011684:Purine Nucleosides; D012313:RNA; D004247:DNA; D004254:DNA Nucleotidyltransferases; D011062:Polynucleotide Adenylyltransferase; D012321:DNA-Directed RNA Polymerases; D014740:Vidarabine; D008239:Lysine; D013936:Thymidine; D014529:Uridine