Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
HPB (Oxford). 2013 Aug;15(8):581-7. doi: 10.1111/hpb.12010. Epub 2012 Dec 27.
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.
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 γH2AX. Gene expression was determined by reverse transcriptase polymerase chain reaction.
FOLFOX treatment was associated with an increase in the number of γH2AX-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.
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.
奥沙利铂为基础的化疗与窦状隙阻塞综合征（SOS）的发生有关，而后者对结直肠癌肝转移（CLM）患者接受肝切除术后的预后不利。本研究旨在确定参与 FOLFOX 化疗药物转运和代谢的基因表达水平如何影响 CLM 小鼠模型中的组织损伤。
在 C57/B16 小鼠中建立实验性 CLM，并给予 FOLFOX 化疗。3 周后，处死动物并从肝脏、脾脏和肿瘤组织中提取 RNA。通过免疫组化检测 γH2AX 评估 DNA 损伤。通过逆转录聚合酶链反应（RT-PCR）确定基因表达。
FOLFOX 治疗与脾脏（P<0.01）和肿瘤组织（P<0.01）中 γH2AX 阳性细胞数量增加有关，但肝脏中无此现象。FOLFOX 治疗后组织对损伤的抵抗力与铜转运体 ATP7B 的高表达有关。与 5-氟尿嘧啶代谢或 DNA 修复相关的基因表达差异与组织损伤的严重程度无关。
高水平的 ATP7B 表达与 FOLFOX 化疗后组织损伤的抵抗力有关。ATP7B 基因的多态性可能解释了接受奥沙利铂为基础的化疗后患者发生 SOS 的不同易感性。
