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An experimental study to identify the potential role of pharmacogenomics in determining the occurrence of oxaliplatin-induced liver injury

Lookup NU author(s): Stuart Robinson, Professor Jelena Mann, Professor Derek Manas, Professor Derek Mann, Steven White


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Background: Oxaliplatin-based chemotherapy has been linked to the development of sinusoidal obstruction syndrome (SOS), which is detrimental to outcome after liver resection for colorectal liver metastases (CLM). The aim of this study was to determine how the expression of genes involved in the transport and metabolism of FOLFOX chemotherapy impacts on tissue injury in a murine model of CLM.Methods: Experimental CLM was established in C57/B16 mice and treated with FOLFOX chemotherapy. After 3 weeks, the animals were killed and RNA extracted from liver, spleen and tumour tissue. DNA damage was assessed by immunohistochemistry for gamma H2AX. Gene expression was determined by reverse transcriptase polymerase chain reaction.Results: FOLFOX treatment was associated with an increase in the number of gamma H2AX-positive cells in both the spleen (P < 0.01) and tumour tissue (P < 0.01), but not the liver. Tissue resistance to injury following FOLFOX was associated with high expression of the copper transporter ATP7B. Differences in the expression of genes related to 5-fluorouracil metabolism or DNA repair did not correlate with the severity of tissue injury.Conclusions: High levels of expression of ATP7B are associated with resistance to tissue injury following FOLFOX chemotherapy. Polymorphisms in the ATP7B gene may explain varying susceptibility to SOS among patients following oxaliplatin-based chemotherapy.

Publication metadata

Author(s): Robinson SM, Mann J, Manas DM, Mann DA, White SA

Publication type: Article

Publication status: Published

Journal: HPB

Year: 2013

Volume: 15

Issue: 8

Pages: 581-587

Print publication date: 01/08/2013

Online publication date: 27/12/2012

Acceptance date: 17/10/2012

ISSN (print): 1365-182X

ISSN (electronic): 1477-2574

Publisher: Wiley-Blackwell


DOI: 10.1111/hpb.12010


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Funder referenceFunder name
WT090974MAWellcome Trust Clinical Research Training Fellowship