Mechanisms of Chemotherapy-Induced Peripheral Pain

描述(申请人提供)：周围神经病是每一种主要一线化疗药物用于治疗所有最常见类型癌症的主要剂量限制因素，因此每年影响数十万患者。神经病会导致如此痛苦，以至于许多患者将放弃潜在的根治疗法，直接影响他们的生存。化疗引起的疼痛难以治疗，通常持续存在于癌症幸存者身上，限制了生活质量、康复和恢复生产。该项目持续的长期目标是确定化疗引起的神经病理性疼痛(CIPN)的机制，并确定缓解或预防其潜在的治疗干预措施。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治疗的无肿瘤动物身上进行测试。具体目标1将决定 患者对紫杉醇或奥沙利铂诱导的CIPN的敏感性取决于四肢的基线神经密度。最初的工作假设是，开始时指尖或脚趾中MC密度最低的患者将是那些最有可能发展为CIPN的患者。具体目的2将确定背根神经节趋化因子/细胞因子信号的激活是否是紫杉醇和奥沙利铂诱导的化疗神经病外周机制的关键早期步骤。行为、免疫组织化学和生化方法将被用来确定趋化因子/细胞因子信号在早期的作用，而不是在两种大鼠化学神经病模型的中期和晚期。最初的工作假设是MCP-1/CCR2是紫杉醇CIPN的关键早期介质，而IL-6是晚期介质。进一步的假设是相似的细胞因子在奥沙利铂CIPN中起关键作用。具体目标3将确定在化学神经病模型的背根节中招募的第二信使系统。将再次使用行为、免疫组织化学和生化方法。最初的工作假设是，与趋化因子/细胞因子信号相关的信使是关键信号。总而言之，该项目将确定化疗引起的周围神经病变的机制，确定患者的危险因素和潜在的新的近期保护和治疗候选方案。因此，该项目将影响接受紫杉醇或奥沙利铂治疗的数千名癌症患者的生活质量、存活率和恢复生产力。

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.