Abstract
An estimated thirteen million new cancers are diagnosed every year and in many cases patients will be treated with chemotherapeutic agents, either with curative intent or to prolong life and alleviate symptoms. Historically the dose limiting side-effect of these compounds was immune- and myelosupression, however, as our ability to manage these has improved, a secondary dose-limiting side-effect of these compounds has been revealed: neurotoxicity.Several anti-neoplastics, including the vinca alkaloids, cause a distal, bilateral and symmetrical painful peripheral neuropathy primarily affecting the longest neurons of the extremities. The key symptom of this condition is pain, yet current therapies are ineffective in alleviating this; the average patient rates their pain as a seven out of ten in severity and pain results cessation of treatment in up to 40% of patients.
One of the main pitfalls in the development of analgesics for this condition is that little is understood about the mechanism by which chemotherapy causes neuropathy. Thus, I have aimed to delineate a novel pathway of the mechanism by which vincristine sulphate (VCR) induces painful peripheral neuropathy.
The pathway delineated is based on the observation that there is significant monocyte-macrophage infiltration of the peripheral nerves following VCR administration, in a temporal profile similar to that of the onset of mechanical allodynia (a painful response to normally innocuous stimuli) in the mouse, and that depletion of monocyte/macrophages prior to VCR administration attenuates allodynia. Whilst this depletion is not a viable therapeutic option for patients, it has led us to investigate of the contribution to the development of pain of the CX3CR1 receptor, the level of expression of which is the defining characteristic of monocyte/macrophages.
We have established that CX3CR1 plays a critical role in the development of VCR-neuropathy; mice devoid of CX3CR1 exhibit a delay in the onset of allodynia and a reduction in VCR-induced nerve infiltration of CX3CR1+ monocyte/macrophages. We have demonstrated that this infiltration is likely a result of up-regulation of monocyte adhesion molecules on the endothelial cells lining blood vessels. Furthermore, we suggest that at the blood-nerve interface CX3CR1+ monocytes/macrophages are activated by CX3CL1, endogenously expressed on endothelial cells, promoting the production of reactive oxygen species, which subsequently activate the TRPA1 receptor on sensory neurons.
This work has led to the conclusion that CX3CR1 antagonists constitute new peripheral targets for the prophylactic treatment of chemotherapy induced painful peripheral neuropathy
| Date of Award | 2013 |
|---|---|
| Original language | English |
| Awarding Institution |
|
| Supervisor | Marzia Malcangio (Supervisor) |