Effects of 1-beta-D-arabinofuranosylcytosine incorporation on eukaryotic DNA template function.
1-beta-D-Arabinofuranosylcytosine (ara-C) incorporates into DNA, and the extent of this incorporation correlates significantly with inhibition of DNA synthesis. The incorporated ara-C residue provides a poor primer terminus for further chain elongation. There is a highly significant relationship between formation of (ara-C) DNA and loss of clonogenic survival. The present studies confirm that incorporation of ara-C into DNA, and not the competitive inhibition of DNA polymerase, is responsible for inducing lethal cellular events. The results also demonstrate that the incorporated ara-C residue is not excised from the DNA strand. Furthermore, the presistence of ara-C residues in DNA inhibits recovery of DNA synthesis following exposure to drug. The relative DNA chain-terminating effect of ara-C provides several mechanisms of action that explain internucleotide and chain terminus positioning of ara-C residues, reinitiation of previously replicated DNA segments, and DNA strand or chromosomal breaks. The precise mechanism of action is dependent upon dose scheduling of this drug.
D000818:Animals; D016590:Aphidicolin; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000378:metabolism* / Q000633:toxicity; D004261:DNA Replication / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics*; D004224:Diterpenes / Q000494:pharmacology*; D007700:Kinetics; D007939:Leukemia L1210 / Q000378:metabolism; D051379:Mice; D013698:Templates, Genetic
D004273:DNA, Neoplasm; D004224:Diterpenes; D003561:Cytarabine; D016590:Aphidicolin