Abstract
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.
Highlights
Oxaliplatin is a 3rd generation compound of the platinum drug family effectively employed for the treatment of colorectal cancer, the third leading cause of death in western countries
We employed neurophysiological and behavioural analysis, neuropathological evaluations of the dorsal root ganglia (DRG), sciatic and caudal nerve and morphometric measures of DRG sensory neurons and of intraepidermal nerve fibers (IENF) to study the extent of functional and structural damages induced by chronic oxaliplatin treatment
To assess the functional status of peripheral nerves, Nerve Conduction Velocity (NCV) were measured in the caudal and digital nerves 3 days after the last oxaliplatin dose
Summary
Three-hundred and thirty-six mice belonging to 1 outbred (CD1) and 5 different inbred (Balb-c, C57BL65, DBA/2J, AJ, FVB) strains aged 10 weeks upon arrival were employed (Envigo, San Pietro al Natisone, Italy). Animals were housed 5 per cage in a limited access animal facility where room temperature and relative humidity were set at 20 ± 2 ̊C and 55 ± 10% respectively. Treated and untreated mice were housed separately. The general condition of the animals was assessed daily. The care and husbandry of animals were in conformity with the institutional guidelines in compliance with national L.vo 26/2014, Gazzetta Ufficiale della Repubblica Italiana, n.61, March 14th 2014) and international laws and policies (European Union directive 2010/63/UE; Guide for the Care and Use of Laboratory Animals, U.S National Research Council, 1996). The Ethics Committee of the University of Milan Bicocca approved the study plan (n. 004874/ 14)
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