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Title: Potential candidate genomic biomarkers of drug induced vascular injury in the rat

Abstract

Drug-induced vascular injury is frequently observed in rats but the relevance and translation to humans present a hurdle for drug development. Numerous structurally diverse pharmacologic agents have been shown to induce mesenteric arterial medial necrosis in rats, but no consistent biomarkers have been identified. To address this need, a novel strategy was developed in rats to identify genes associated with the development of drug-induced mesenteric arterial medial necrosis. Separate groups (n = 6/group) of male rats were given 28 different toxicants (30 different treatments) for 1 or 4 days with each toxicant given at 3 different doses (low, mid and high) plus corresponding vehicle (912 total rats). Mesentery was collected, frozen and endothelial and vascular smooth muscle cells were microdissected from each artery. RNA was isolated, amplified and Affymetrix GeneChip Registered-Sign analysis was performed on selectively enriched samples and a novel panel of genes representing those which showed a dose responsive pattern for all treatments in which mesenteric arterial medial necrosis was histologically observed, was developed and verified in individual endothelial cell- and vascular smooth muscle cell-enriched samples. Data were confirmed in samples containing mesentery using quantitative real-time RT-PCR (TaqMan Trade-Mark-Sign ) gene expression profiling. In addition, the performance ofmore » the panel was also confirmed using similarly collected samples obtained from a timecourse study in rats given a well established vascular toxicant (Fenoldopam). Although further validation is still required, a novel gene panel has been developed that represents a strategic opportunity that can potentially be used to help predict the occurrence of drug-induced mesenteric arterial medial necrosis in rats at an early stage in drug development. -- Highlights: Black-Right-Pointing-Pointer A gene panel was developed to help predict rat drug-induced mesenteric MAN. Black-Right-Pointing-Pointer A gene panel was identified following treatment of rats with 28 different toxicants. Black-Right-Pointing-Pointer There was a strong correlation of genes and histologic evidence of mesenteric MAN. Black-Right-Pointing-Pointer Many genes were also regulated prior to histologic evidence of arterial effects.« less

Authors:
 [1];  [1];  [1];  [1];  [2];  [2];  [1];  [1]
  1. Department of Safety Assessment, King of Prussia, PA 19406 (United States)
  2. Department of Quantitative Sciences GlaxoSmithKline, King of Prussia, PA 19406 (United States)
Publication Date:
OSTI Identifier:
22212574
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 257; Journal Issue: 2; Other Information: Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACTIN; BIOLOGICAL MARKERS; DOPAMINE; EOSIN; EXTRACELLULAR SPACE; HEMATOXYLIN; INJURIES; LEUCINE; MESENTERY; NECROSIS; ONCOGENES; OXIDASES; POLYMERASE CHAIN REACTION; POLYPEPTIDES; RATS; RECEPTORS; TROPOMYOSIN

Citation Formats

Dalmas, Deidre A., E-mail: Deidre.A.Dalmas@gsk.com, Scicchitano, Marshall S., E-mail: Marshall.S.Scicchitano@gsk.com, Mullins, David, E-mail: David.R.Mullins@gsk.com, Hughes-Earle, Angela, E-mail: Angela.R.Hughes-Earle@gsk.com, Tatsuoka, Kay, E-mail: Kay.S.Tatsuoka@gsk.com, Magid-Slav, Michal, E-mail: Michal.M.Magid-Slav@gsk.com, Frazier, Kendall S., E-mail: Kendall.S.Frazier@gsk.com, and Thomas, Heath C., E-mail: Heath.C.Thomas@gsk.com. Potential candidate genomic biomarkers of drug induced vascular injury in the rat. United States: N. p., 2011. Web. doi:10.1016/J.TAAP.2011.09.015.
Dalmas, Deidre A., E-mail: Deidre.A.Dalmas@gsk.com, Scicchitano, Marshall S., E-mail: Marshall.S.Scicchitano@gsk.com, Mullins, David, E-mail: David.R.Mullins@gsk.com, Hughes-Earle, Angela, E-mail: Angela.R.Hughes-Earle@gsk.com, Tatsuoka, Kay, E-mail: Kay.S.Tatsuoka@gsk.com, Magid-Slav, Michal, E-mail: Michal.M.Magid-Slav@gsk.com, Frazier, Kendall S., E-mail: Kendall.S.Frazier@gsk.com, & Thomas, Heath C., E-mail: Heath.C.Thomas@gsk.com. Potential candidate genomic biomarkers of drug induced vascular injury in the rat. United States. doi:10.1016/J.TAAP.2011.09.015.
Dalmas, Deidre A., E-mail: Deidre.A.Dalmas@gsk.com, Scicchitano, Marshall S., E-mail: Marshall.S.Scicchitano@gsk.com, Mullins, David, E-mail: David.R.Mullins@gsk.com, Hughes-Earle, Angela, E-mail: Angela.R.Hughes-Earle@gsk.com, Tatsuoka, Kay, E-mail: Kay.S.Tatsuoka@gsk.com, Magid-Slav, Michal, E-mail: Michal.M.Magid-Slav@gsk.com, Frazier, Kendall S., E-mail: Kendall.S.Frazier@gsk.com, and Thomas, Heath C., E-mail: Heath.C.Thomas@gsk.com. Thu . "Potential candidate genomic biomarkers of drug induced vascular injury in the rat". United States. doi:10.1016/J.TAAP.2011.09.015.
@article{osti_22212574,
title = {Potential candidate genomic biomarkers of drug induced vascular injury in the rat},
author = {Dalmas, Deidre A., E-mail: Deidre.A.Dalmas@gsk.com and Scicchitano, Marshall S., E-mail: Marshall.S.Scicchitano@gsk.com and Mullins, David, E-mail: David.R.Mullins@gsk.com and Hughes-Earle, Angela, E-mail: Angela.R.Hughes-Earle@gsk.com and Tatsuoka, Kay, E-mail: Kay.S.Tatsuoka@gsk.com and Magid-Slav, Michal, E-mail: Michal.M.Magid-Slav@gsk.com and Frazier, Kendall S., E-mail: Kendall.S.Frazier@gsk.com and Thomas, Heath C., E-mail: Heath.C.Thomas@gsk.com},
abstractNote = {Drug-induced vascular injury is frequently observed in rats but the relevance and translation to humans present a hurdle for drug development. Numerous structurally diverse pharmacologic agents have been shown to induce mesenteric arterial medial necrosis in rats, but no consistent biomarkers have been identified. To address this need, a novel strategy was developed in rats to identify genes associated with the development of drug-induced mesenteric arterial medial necrosis. Separate groups (n = 6/group) of male rats were given 28 different toxicants (30 different treatments) for 1 or 4 days with each toxicant given at 3 different doses (low, mid and high) plus corresponding vehicle (912 total rats). Mesentery was collected, frozen and endothelial and vascular smooth muscle cells were microdissected from each artery. RNA was isolated, amplified and Affymetrix GeneChip Registered-Sign analysis was performed on selectively enriched samples and a novel panel of genes representing those which showed a dose responsive pattern for all treatments in which mesenteric arterial medial necrosis was histologically observed, was developed and verified in individual endothelial cell- and vascular smooth muscle cell-enriched samples. Data were confirmed in samples containing mesentery using quantitative real-time RT-PCR (TaqMan Trade-Mark-Sign ) gene expression profiling. In addition, the performance of the panel was also confirmed using similarly collected samples obtained from a timecourse study in rats given a well established vascular toxicant (Fenoldopam). Although further validation is still required, a novel gene panel has been developed that represents a strategic opportunity that can potentially be used to help predict the occurrence of drug-induced mesenteric arterial medial necrosis in rats at an early stage in drug development. -- Highlights: Black-Right-Pointing-Pointer A gene panel was developed to help predict rat drug-induced mesenteric MAN. Black-Right-Pointing-Pointer A gene panel was identified following treatment of rats with 28 different toxicants. Black-Right-Pointing-Pointer There was a strong correlation of genes and histologic evidence of mesenteric MAN. Black-Right-Pointing-Pointer Many genes were also regulated prior to histologic evidence of arterial effects.},
doi = {10.1016/J.TAAP.2011.09.015},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 257,
place = {United States},
year = {Thu Dec 15 00:00:00 EST 2011},
month = {Thu Dec 15 00:00:00 EST 2011}
}