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Correlation of Simultaneous Differential Gene Expression in the Blood and Heart with Known Mechanisms of Adriamycin-Induced Cardiomyopathy in the Rat

Drug Safety, Toxicogenomics, GlaxoSmithKline, Inc, Research Triangle Park, North Carolina 27709, hrb25873{at}gsk.com

Hong Ni

Drug Safety, Toxicogenomics, GlaxoSmithKline, Inc, Research Triangle Park, North Carolina 27709

Gina Benavides

Drug Safety, Toxicogenomics, GlaxoSmithKline, Inc, Research Triangle Park, North Carolina 27709

Lawrence Yoon

Drug Safety, Toxicogenomics, GlaxoSmithKline, Inc, Research Triangle Park, North Carolina 27709

Karim Hyder

Clontech Laboratories, Inc, Palo Alto, California 94303

Jaisri Giridhar

Medicine Safety Evaluation, GlaxoSmithKline, Inc, Research Triangle Park, North Carolina 27709

Guy Gardner

Medicine Safety Evaluation, GlaxoSmithKline, Inc, Research Triangle Park, North Carolina 27709

Ronald D. Tyler

Drug Safety, Toxicogenomics, GlaxoSmithKline, Inc, Research Triangle Park, North Carolina 27709

Kevin T. Morgan

Drug Safety, Toxicogenomics, GlaxoSmithKline, Inc, Research Triangle Park, North Carolina 27709

As the genomes of mammalian species become sequenced and gene functions are ascribed, the use of differential gene expression (DGE) to evaluate organ function will become common in the experimental evaluation of new drug therapies. The ability to translate this technology into useful information for human exposures depends on tissue sampling that is impractical or generally not possible in man. The possibility that the DGE of nucleated cells, reticulocytes, or platelets in blood may present the necessary link with target organ toxicity provides an opportunity to correlate preclinical with clinical outcomes. Adriamycin is highly effective alone and more frequently in combination with other chemotherapeutic agents in the treatment of a variety of susceptible malignancies. Adriamycin-induced cardiomyopathy was examined as an endpoint to measure the utility of DGE on whole blood as a predictor of cardiac toxicity. Statistically significant gene changes were observed between relevant blood and cardiac gene profiles that corroborated the accepted mechanisms of toxicity (oxidative stress, effects on carnitine transport, DNA intercalation). There were, however, clear indications that other target organs (bone marrow and intestinal tract) were affected. The divergent expression of some genes between the blood and the heart on day 7 may also indicate the timing and mechanism of development of the cardiomyopathy and confirm current therapeutic approaches for its prevention. The data demonstrate that whole blood gene expression particularly in relation to oxidative stress, in conjunction with standard hematology and clinical chemistry, may be useful in monitoring and predicting cardiac damage secondary to adriamycin administration. Appendices A & B, referenced in this paper, are not printed in this issue of Toxicologic Pathology. They are available as downloadable text files at http://taylorandfrancis.metapress.com/openurl.asp?genre = journal&issn = 0192-6233. To access them, click on the issue link for 30(4), then select this article. A download option appears at the bottom of this abstract. In order to access the full article online, you must either have an individual subscription or a member subscription accessed through www.toxpath.org.

Key Words: Blood • heart • gene expression • doxorubicin.

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