Mechanisms of Chemotherapy-Induced Peripheral Pain

化疗引起的周围疼痛的机制

• 批准号: 8401100
• 负责人: Patrick M Dougherty
• 金额: $ 38.08万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8401100
• 关键词: Affect; Animals; Award; Behavioral; Biochemical; CCL2 gene; Cancer Patient; Cancer Survivor; Chronic; Complication; Cytokine Signaling; Data; Development; Distress; Dose-Limiting; Drops; Drug usage; Fingers; Goals; Hour; Human; Hyperalgesia; Immune Sera; Interleukin-1; Interleukin-6; Limb structure; MAPK3 gene; Mediator of activation protein; Microscopy; Minocycline; Modeling; Neurons; Neuropathy; Paclitaxel; Pain; Patients; Pattern; Peripheral; Peripheral Nervous System Diseases; Predisposition; Prevention; Productivity; Quality of life; Rattus; Recruitment Activity; Refractory; Rehabilitation therapy; Reporting; Risk; Risk Factors; Role; STAT3 gene; Second Messenger Systems; Sensory; Signal Transduction; Skin; Spinal Ganglia; Staging; Symptoms; TNF gene; Testing; Therapeutic Intervention; Time; Toes; Up-Regulation; Work; cancer therapy; cancer type; chemokine; chemotherapy; cytokine; density; falls; human MAPK14 protein; in vivo; nerve supply; oxaliplatin; painful neuropathy; prevent; response; second messenger; tumor; volunteer

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. PUBLIC HEALTH RELEVANCE: 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. This project will define mechanisms of chemotherapy-induced peripheral neuropathy; identify patient risk factors and potential new near-term protective and treatment candidates.

描述（由申请人提供）：周围神经病变是针对所有最常见癌症类型的每种主要一线化疗药物的主要剂量限制因素，因此每年影响数十万患者。神经病变会造成如此痛苦，以至于许多患者会放弃潜在的治疗方法，从而直接影响他们的生存。化疗引起的疼痛难以治疗，并且常常持续存在于癌症幸存者中，限制了生活质量、康复和生产力的恢复。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。实现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 将确定 患者对紫杉醇或奥沙利铂诱导的 CIPN 的敏感性是否取决于四肢的基线神经支配密度。最初的工作假设是，开始时指尖或脚趾 MC 密度最低的患者最有可能发生 CIPN。具体目标 2 将确定背根神经节中趋化因子/细胞因子信号传导的激活是否是紫杉醇和奥沙利铂诱导的化学神经病的外周机制的关键早期步骤。将使用行为、免疫组织化学和生化方法来定义趋化因子/细胞因子信号传导在大鼠两种化学神经病模型的早期而不是中期和晚期的作用。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。进一步假设类似的细胞因子介质是奥沙利铂 CIPN 的关键。具体目标 3 将确定化学神经病模型中 DRG 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/细胞因子信号传导相关的信使是关键信号。总之，该项目将定义化疗引起的周围神经病变的机制，确定患者危险因素和潜在的新的近期保护和治疗候选者。因此，该项目将影响数千名接受紫杉醇或奥沙利铂治疗的癌症患者的生活质量、生存率和生产力恢复。 公共健康相关性：周围神经病变是针对所有最常见癌症类型的每种主要一线化疗药物的主要剂量限制因素，因此每年影响数十万患者。神经病变会造成如此痛苦，以至于许多患者会放弃潜在的治疗方法，从而直接影响他们的生存。该项目将明确化疗引起的周围神经病变的机制；确定患者风险因素和潜在的新的近期保护和治疗候选者。