Cancer's role in chemotherapy-induced neuropathy.

Abstract

e24064 Background: For the constellation of neurological disorders known as chemotherapy-induced neuropathy, mechanistic understanding, and treatment remain deficient. This might be due to the fact that studies on the effects of chemotherapies on the nervous system have utilized experimental models that exclude cancer perhaps due to the presumption that chemotherapy alone explains the neuropathology. However, the convergence of cancer and chemotherapy on the same biological processes seems likely to yield non-linear interactions. This led us to hypothesize that clinically relevant neuropathy emerges from codependent actions of cancer and chemotherapy. Methods: We established a clinically-relevant animal model of chronic sensory neuropathy in rats with cancer (adenomatous polyposis coli in rat colon: Apc+/Pirc) and age-matched animals without cancer ( ApcWT) that were randomly assigned to receive a human-scaled course of oxaliplatin (OX) or control treatment (4 groups). We quantified behavioral deficits during precision ladder walking, a validated measure of locomotor performance. Neuronal signaling was measured during terminal in vivo experiments to examine the response of sensory neurons to physiologically-relevant stimuli. We defined statistical significance as when 95% of a highest density interval (HDI) of posterior probabilities do not overlap (hierarchical Bayesian modeling). Results: Apc+/Pirc+OX (n = 11) rats exhibited significantly higher error rate (19.2±5.6%, 95%HDI) during precision ladder walking in comparison to ApcWT+control (2.4±2.7%: n = 9) or Apc+/Pirc +control (2.5±2.9%: n = 7) and significantly exceeded the error rate observed in animals treated with OX alone (8.4±3.1%: n = 10). In contrast to the observations in all other groups, we found drastically impaired neuronal signaling in Apc+/Pirc+OX rats which manifested as significantly reduced sensitivity and attenuated static and dynamic firing patterns (95%HDI). Conclusions: We present the first evidence that chronic neuropathy cannot be explained by the effects of chemotherapy alone but instead depend on non-linear interactions between cancer and chemotherapy. This understanding is a prerequisite for developing meaningful treatment or prevention of neuropathy.