investigator_user investigator user funding collaborators pending menu bell message arrow_up arrow_down filter layers globe marker add arrow close download edit facebook info linkedin minus plus save share search sort twitter remove user-plus user-minus
  • Project leads
  • Collaborators

Oxidative stress as a causal mechanism for chemotherapy-induced pain

Sarah Flatters

0 Collaborator(s)

Funding source

Wellcome Trust (WT)
Peripheral neurotoxicity is the major dose-limiting side effect of paclitaxel/oxaliplatin chemotherapy causing pain in hands and feet, resulting in the cessation of otherwise effective (i.e. anti-tumour) chemotherapy. There is no treatment for paclitaxel/oxaliplatin-induced pain and little knowledge of its causal mechanisms. We hypothesize that paclitaxel/oxaliplatin-induced pain is caused by reactive oxygen species (ROS) generation in sensory afferents. Transient receptor potential A1 (TRPA1) i s a known sensor of neuronal ROS and linked to pain perception. Thus we further hypothesise that paclitaxel-/oxaliplatin-induced ROS evokes pain via TRPA1. Using translational rodent models of paclitaxel/oxaliplatin-induced pain, which replicate the clinical scenario of multiple treatment cycles evoking mechanical/cold hypersensitivities, our key goals are: 1) Evaluate the therapeutic effect of inhibiting ROS in vivo to reverse or prevent paclitaxel-/oxaliplatin-induced pain. 2) Establish if ROS levels are elevated in sensory afferents, and in which neuronal/cellular subpopulations, following paclitaxel/oxaliplatin administration. ROS expression will be correlated to paclitaxel-/oxaliplatin-induced pain timecourses, identifying the neuronal/cellular target(s) and required timing of ROS inhibition to achieve greatest therapeutic benefit. 3) Investigate if paclitaxel/oxaliplatin-induced ROS evokes pain via TRPA1. TRPA1 antagonists/knockout mice will assess if TRPA1 blockade affect s the genesis of paclitaxel/oxaliplatin-induced pain. Fluorescence imaging will identify if paclitaxel-/oxaliplatin-induced ROS signal via TRPA1 channels.

Related projects