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Series GSE19290 Query DataSets for GSE19290
Status Public on Jan 01, 2010
Title Cardiotoxicity of tubulin binders
Organism Rattus norvegicus
Experiment type Expression profiling by array
Summary The use of tubulin binders (TBs) in oncology indications often is associated with cardiotoxicity, the mechanism of which has not been elucidated. We observed that a single administration of TBs to rats caused an increase in the number of mitotic figures in the myocardial interstitium after 24 hours. We therefore hypothesized that interstitial cells are the primary target of TBs. To test this hypothesis, we evaluated the acute effects of a single intravenous administration of 3 reference TBs, colchicine (0.2 and 2 mg/kg), vinblastine (0.5 and 3 mg/kg), and vincristine (0.1 and 1 mg/kg) 6 and 24 hours after dosing. Mitotic arrest was identified at 24 hours in all high-dose groups based on an increase in the number of mitotic figures in the interstitium coupled with a dramatic decrease in the number of Ki67-positive interstitial cells. Analysis of the myocardial transcriptomic data further supported G2/M cell cycle arrest 6 hours after dosing with the high-dose groups of all 3 compounds. Apoptotic figures and an increase in the number of cleaved caspase 3-positive cells were identified at 6 and 24 hours at the highest dose of each compound almost exclusively in interstitial cells; a few cardiomyocytes were affected as well. Transcriptomic data further suggested that some of the affected interstitial cells were endothelial cells based on the up-regulation of genes typically associated with vascular damage and down-regulation of Endothelial Cell-Specific Molecule 1 and Apelin. Taken together, these data identify endothelial cells of the myocardium as the primary target of the cardiotoxicity of TBs and identify cell cycle arrest as the mechanism of this toxicity.
 
Overall design Gene expression was profiled in the myocardium of rats at 6 and 24 hr after a single dose of colchicine, vinblastine or vincristine.
 
Contributor(s) Mikaelian I, Buness A, de Vera-Mudry C, Kanwal C, Coluccio D, Rasmussen E, Downing JC, Char HW, Nicklaus R, Hilton H, Funk J, Hoflack J, Fielden M, Herting F, Suter-Dick L
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Submission date Dec 02, 2009
Last update date Jul 31, 2017
Contact name Charu Kanwal
E-mail(s) charu.kanwal@roche.com
Organization name Hoffman-La Roche
Department RIGG
Street address 340 Kingsland Street
City Nutley
State/province NJ
ZIP/Postal code 07110
Country USA
 
Platforms (1)
GPL1355 [Rat230_2] Affymetrix Rat Genome 230 2.0 Array
Samples (82)
GSM478817 Rat treated with Saline (vehicle) for 6hr, 1
GSM478818 Rat treated with Saline (vehicle) for 6hr, 2
GSM478819 Rat treated with Saline (vehicle) for 6hr, 3
Relations
BioProject PRJNA120375

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE19290_RAW.tar 221.6 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table
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