Mechanisms of Chemotherapy-Induced Peripheral Pain

描述（由申请人提供）：周围神经病变是每一种主要一线化疗药物的主要剂量限制因素，用于治疗所有最常见的癌症类型，因此每年影响数十万患者。神经病变引起的痛苦，许多患者将退出潜在的治愈治疗，直接影响他们的生存。化疗引起的疼痛是难以治疗的，并且经常持续存在于癌症幸存者中，限制了生活质量、康复和恢复生产力。该项目的长期目标是确定化疗引起的神经性疼痛（CIPN）的机制，并确定缓解或预防其潜在的治疗干预措施。针对这一目标的三个具体目标将在接受癌症治疗的人类或接受紫杉醇或奥沙利铂的无肿瘤动物中进行测试。具体目标1将决定

DESCRIPTION (provided by applicant): Peripheral neuropathy is the principal dose-limiting factor for each of the major frontline chemotherapeutic drugs used against all the most common types of cancer and hence affects hundreds of thousands of patients each year. Neuropathy causes such distress that many patients will drop out of potentially curative therapy, directly impacting their survival. Chemotherapy-induced pain is refractory to treatment and often persists in cancer survivors limiting quality of life, rehabilitation and the return to productivit. The continuing long-term goal of this project is to determine the mechanisms of chemotherapy- induced neuropathic pain (CIPN) and identify potential therapeutic interventions for its relief or prevention. Three specific aims toward this goal will be tested in humans undergoing cancer therapy or in tumor-free animals receiving paclitaxel or oxaliplatin. Specific Aim 1 will determine whether patient susceptibility to paclitaxel or oxaliplatin induced CIPN is dependent upon baseline innervation density of the extremities. The initial working hypothesis will be that patients who start with the lowest MC density in the fingertips or toes will be those most likely t develop CIPN. Specific Aim 2 will determine whether activation of chemokine/cytokine signaling in the dorsal root ganglia are key early steps in peripheral mechanisms of paclitaxel and oxaliplatin induced chemoneuropathy. Behavioral, immunohistochemical, and biochemical approaches will be used to define the role of chemokine/cytokine signaling in the early as opposed to the mid- and late stages of both models of chemoneuropathy in rats. The initial working hypothesis is that MCP-1/CCR2 are key early mediators of paclitaxel CIPN whereas IL-6 is a late mediator. It is further hypothesized that similar cytokine mediators are key in oxaliplatin CIPN. Specific Aim 3 will determine the second messenger systems that are recruited in the DRG in models of chemoneuropathy. Behavioral, immunohistochemical, and biochemical approaches will again be used. The initial working hypothesis is that the messengers associated with chemokine/cytokine signaling are the key signals. In summary this project will define mechanisms of chemotherapy-induced peripheral neuropathy, identify patient risk factors and potential new near-term protective and treatment candidates. This project will therefore impact on the quality of life, survival and the return to productivity of thousands of cancer patients who receive paclitaxel or oxaliplatin therapy.