Previous studies have demonstrated that @entity2592 ( @entity2592 ) induces an accumulation of Okazaki fragments, while @entity3118 (FaraA) inhibits Okazaki fragment synthesis. We extended these observations in the present study to provide insights into various mechanisms by which these anticancer drugs affect DNA replication and induce genomic instability in @entity1 @entity1778 cells. Neither araC nor FaraA induced a detectable amount of re-replicated DNA in S-phase cells, which indicated that drug-induced alterations in Okazaki fragment synthesis were not accompanied by DNA re-replication. Synthesis on both leading and lagging DNA strands within the @entity517 locus was measured in cells incubated with equitoxic concentrations of araC or FaraA. In araC-treated cells, nascent DNA from the lagging strand was enriched about 5-fold compared with the leading strand. In contrast, FaraA did not induce any replication imbalance. AraC- and FaraA induced changes in the frequency of @entity19598 ( @entity19598 ) resistance and the extent of @entity74 were monitored as markers of drug-induced genomic instability. At concentrations that reduced cloning efficiency by 50% (IC(50)), araC increased the frequency of @entity19598 resistance about 4-fold, while FaraA did not have a significant effect on the frequency of @entity19598 resistance. Pretreatment with araC also increased the extent of @entity74 . We propose that the imbalanced DNA synthesis induced by araC leads to the accumulation of Okazaki fragments on the lagging arms and single-stranded DNA regions on the leading arms of replication forks. The formation of these abnormal replication structures was associated with the generation of genomic instability.

Imbalanced DNA synthesis induced by @entity2592 and @entity3118 in XXXX @entity1778 cells.

@entity1 :: ('9606', 'Species') :: ['human'] @entity517 :: ('4609', 'Gene') :: ['c-myc'] @entity2592 :: ('MESH:D003561', 'Chemical') :: ['cytosine arabinoside', 'araC'] @entity3118 :: ('MESH:C024352', 'Chemical') :: ['fludarabine'] @entity1778 :: ('MESH:D007938', 'Disease') :: ['CEM leukemia'] @entity19598 :: ('MESH:C013195', 'Chemical') :: ['N-(phosphonacetyl)-l-aspartate', 'PALA'] @entity74 :: ('MESH:D030342', 'Disease') :: ['CAD gene amplification']
@entity1 :: (9606,Species) :: ['human']
