Painful neuropathy is the principal dose-limiting factor in chemotherapy with vincristine, bortezomib, andthalidomide. This pain is refractory to treatment and often persists in cancer survivors. The long-term goal ofthis project is to determine the mechanism of chemotherapy-induced pain and identify potential therapeuticinterventions for its relief and prevention. Several key tenets of a working model of chemoneuropathy will betested in three specific aims conducted in humans who are undergoing chemotherapy for multiple myelomaor acute leukemia and/or in tumor-free animals treated with one of the same compounds.
Specific Aim i will test the hypothesis that vincristine, bortezomib and thalidomide induce or unmask elevated levels ofproinflammatory cytokines and increased levels of activated NF-KB.
Specific Aim 2 will test the hypothesisthat vincristine, bortezomib and thalidomide have shared effects on primary afferent fibers leading toneuropathic pain.
Specific Aim 3 will test the hypothesis that chemotherapy-induced neuropathy isproduced by the action of pro-inflammatory cytokines in specific body compartments. This will be tested inhumans and animals. In summary this project will define mechanisms of chemotherapy-induced pain,identify near-term treatment candidates, and establish the key databases needed to design and justify clinicaltrials that will be the subject of follow-up studies. This project will provide direct evidence for severalimportant basic tenets of a pathophysiological model of chemo-neuropathy that in turn will define importantnew targets for therapy and intervention. This project will therefore impact on the quality of life, survival andthe return to productivity of nearly all cancer patients who receive vincristine, thalidomide or bortezomib.
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