Susceptibility of different mouse strains to oxaliplatin peripheral neurotoxicity: Phenotypic and genotypic insights.
Susceptibility of different mouse strains to oxaliplatin peripheral neurotoxicity: Phenotypic and genotypic insights.
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DOI：
10.1371/journal.pone.0186250
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Carozzi VA
中科院分区：
文献类型：
--
作者：
Marmiroli P;Riva B;Pozzi E;Ballarini E;Lim D;Chiorazzi A;Meregalli C;Distasi C;Renn CL;Semperboni S;Morosi L;Ruffinatti FA;Zucchetti M;Dorsey SG;Cavaletti G;Genazzani A;Carozzi VA
周围神经毒性是奥沙利铂治疗癌症最令人痛苦的副作用之一。事实上，大多数接受奥沙利铂治疗的患者均发生急性和/或慢性重度感觉性周围神经病变。然而，尽管合并症、癌症分期、人口统计学和治疗方案相似，但患者发生奥沙利铂诱导的周围神经毒性，严重程度显著不同。这表明个体遗传变异性，可用于收集奥沙利铂神经毒性的机制见解。我们表征了不同小鼠品系对奥沙利铂神经毒性的易感性，研究了暴露于相同奥沙利铂方案的6种遗传不同小鼠品系（Balb-c、C57 BL 6、DBA/2 J、AJ、FVB和CD 1）的背根神经节中神经病变和基因表达谱的表型特征。使用全基因组表达分析测定来自每个小鼠品系的背根神经节中的差异基因表达，并通过RT-PCR分析验证所选基因。不同菌株对奥沙利铂的表型应答一致差异的证明值得关注，可根据预定义的读出参数选择适当的菌株。进一步研究基因表达变化与奥沙利铂诱导的神经毒性表型之间的相关性，将有助于更深入地研究奥沙利铂神经毒性的分子机制。
Peripheral neurotoxicity is one of the most distressing side effects of oxaliplatin therapy for cancer. Indeed, most patients that received oxaliplatin experience acute and/or chronic severe sensory peripheral neuropathy. However, despite similar co-morbidities, cancer stage, demographics and treatment schedule, patients develop oxaliplatin-induced peripheral neurotoxicity with remarkably different severity. This suggests individual genetic variability, which might be used to glean the mechanistic insights into oxaliplatin neurotoxicity. We characterized the susceptibility of different mice strains to oxaliplatin neurotoxicity investigating the phenotypic features of neuropathy and gene expression profiles in dorsal root ganglia of six genetically different mice strains (Balb-c, C57BL6, DBA/2J, AJ, FVB and CD1) exposed to the same oxaliplatin schedule. Differential gene expression in dorsal root ganglia from each mice strain were assayed using a genome-wide expression analysis and selected genes were validated by RT-PCR analysis. The demonstration of consistent differences in the phenotypic response to oxaliplatin across different strains is interesting to allow the selection of the appropriate strain based on the pre-defined read-out parameters. Further investigation of the correlation between gene expression changes and oxaliplatin-induced neurotoxicity phenotype in each strain will be useful to deeper investigate the molecular mechanisms of oxaliplatin neurotoxicity.
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