Editor's Choice Article for January 2014

Environmental and Molecular Mutagenesis (EMM) Editor's Choice - January 2014

The Editor's Choice for January is “Genotoxicity of Doxorubicin in F344 Rats by Combining the Comet Assay, Flow-Cytometric Peripheral Blood Micronucleus Test, and Pathway-Focused Gene Expression Profiling” by Mugimane G. Manjanatha, Michelle E. Bishop, Mason G. Pearce, Rohan Kulkarni, Lascelles E. Lyn-Cook, and Wei Ding.

Doxorubicin is an effective and widely-used anti-cancer drug.  Unfortunately, cardiotoxicity is a serious, adverse effect caused by Doxorubicin treatment. As a first step toward establishing whether Doxorubicin’s anti-tumor activity can be separated from its cardiotoxic effects, Manjanatha and colleagues performed a detailed analysis of Doxorubicin’s genotoxicity in the cardiac tissue of exposed rats.  They established how Doxrubicin dose related to the drug’s ability to induce DNA damage and strand breaks using enzyme-modified Comet assays (Fpg, hOGG1, and Endo III), along with the standard alkaline comet assay.  They examined changes in cardiac tissue histopathology and changes in gene expression associated with Doxorubicin treatment, as well as the induction of micronuclei in peripheral blood erythrocytes.  The enzyme modified Comet assays, which convert oxidized nucleobases into DNA strand breaks, showed significant induction, whereas no significant induction was detected using the standard alkaline Comet assay.  From this the authors concluded that Doxorubicin-induced cardiotoxicity may reflect the sensitivity of this tissue to oxidative stress.  The gene expression analysis identified significant induction of transcripts associated with cell cycle arrest, DNA damage response, and DNA repair, including base excision repair (Parp1, Parp2) and double-strand break repair (Rad50, Rad52, Xrcc2).  Based on the totality of the data, the authors propose that Doxorubicin-induced double-strand breaks may be repaired relatively rapidly, whereas oxidative DNA damage may persist and contribute to the Doxorubicin’s cardiotoxicity.

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