Document Detail

Differential cell cycle-specificity for chromosomal damage induced by merbarone and etoposide in V79 cells.
MedLine Citation:
PMID:  17174356     Owner:  NLM     Status:  MEDLINE    
Merbarone, a topoisomerase II (topo II) inhibitor which, in contrast to etoposide, does not stabilize topo II-DNA cleavable complexes, was previously shown to be a potent clastogen in vitro and in vivo. To investigate the possible mechanisms, we compared the cell cycle-specificity of the clastogenic effects of merbarone and etoposide in V79 cells. Using flow cytometry and BrdU labeling techniques, etoposide was shown to cause a rapid and persistent G2 delay while merbarone was shown to cause a prolonged S-phase followed by a G2 delay. To identify the stages which are susceptible to DNA damage, we performed the micronucleus (MN) assay with synchronized cells or utilized a combination of BrdU pulse labeling and the cytokinesis-blocked MN assay with non-synchronized cells. Treatment of M phase cells with either agent did not result in increased MN formation. Etoposide but not merbarone caused a significant increase in MN when cells were treated during G2 phase. When treated during S-phase, both chemicals induced highly significant increases in MN. However, the relative proportion of MN induced by merbarone was substantially higher than that induced by etoposide. Both chemicals also caused significant increases in MN in cells that were treated during G1 phase. To confirm the observations in the MN assay, first division metaphases were evaluated in the chromosome aberration assay. The chromosomes of cells treated with merbarone and etoposide showed increased frequencies of both chromatid- and chromosome-type of aberrations. Our findings indicate that while etoposide causes DNA damage more evenly throughout the G1, S and G2 phases of the cell cycle, an outcome which may be closely associated with topo II-mediated DNA strand cleavage, merbarone induces DNA breakage primarily during S-phase, an effect which is likely due to the stalling of replication forks by inhibition of topo II activity.
Ling Wang; Shambhu K Roy; David A Eastmond
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Publication Detail:
Type:  Evaluation Studies; Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-12-15
Journal Detail:
Title:  Mutation research     Volume:  616     ISSN:  0027-5107     ISO Abbreviation:  Mutat. Res.     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-02-09     Completed Date:  2007-05-02     Revised Date:  2010-11-02    
Medline Journal Info:
Nlm Unique ID:  0400763     Medline TA:  Mutat Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  70-82     Citation Subset:  IM    
Environmental Toxicology Graduate Program, 2109 Biological Sciences Building, University of California, Riverside, CA 92521, USA.
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MeSH Terms
Antineoplastic Agents, Phytogenic / toxicity
Cell Cycle*
Cell Line
Chromosome Aberrations*
DNA Topoisomerases, Type II / antagonists & inhibitors
Enzyme Inhibitors / pharmacology
Etoposide / toxicity*
Micronuclei, Chromosome-Defective
Micronucleus Tests
Thiobarbiturates / toxicity*
Time Factors
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/Enzyme Inhibitors; 0/Thiobarbiturates; 33419-42-0/Etoposide; 97534-21-9/merbarone; EC Topoisomerases, Type II

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