Mechanisms of Cancer Therapy-Induced Pain

描述（由申请人提供）：疼痛性神经病变是主要的剂量限制因素，需要停止使用长春新碱、紫杉醇和顺铂进行化疗，这是用于多种肿瘤的一线化疗药物，包括白血病、肺癌和乳腺癌，这些肿瘤在美国最常见。此外，这种疼痛对治疗是难治的，并且经常在癌症幸存者中持续存在。该项目的长期目标是确定化疗引起的疼痛的机制，并确定缓解和预防其潜在的治疗干预措施。与这一目标相关的三个假设将在三个特定目标中进行测试，这些目标由在接受或正在接受长春新碱、紫杉醇或顺铂化疗的人类和用相同化合物治疗的动物中进行的互补研究组成。假设1：长春新碱、紫杉醇和顺铂对初级传入纤维功能有共同的影响，导致神经性疼痛。这一假设将仅在人类身上进行验证。特异性目的1.1：在癌症患者化疗期间，将通过定量感觉测试跟踪原发性传入功能。出现疼痛的患者的结果将与正常志愿者的结果以及没有出现疼痛的患者的数据进行对比。假设2：长春新碱、紫杉醇和顺铂对导致神经性疼痛的促炎细胞因子有共同的作用。这一假设将在人类和动物身上得到验证。特异性目标2.1：在接受化疗的患者中，随着时间的推移，将跟踪血清细胞因子水平、定量感觉功能和症状评估。出现疼痛的患者的结果将与正常对照和未出现疼痛的患者进行对比。特异性目标2.2：在动物中，随着化疗时间的推移，将测量血清、脊髓、背根神经节和足底皮肤中细胞因子的表达。假设3：化疗引起的神经病变是由促炎细胞因子在特定体室中的作用产生的。这将在动物身上单独进行试验。特异性目的3.1：化疗后个体细胞因子升高，注入脊髓、背根神经节和皮肤神经末梢周围，重现化疗神经病的行为体征。特异性目标3.2：细胞因子拮抗剂将与化疗药物同时全身性给药并进入局部体室，以防止化疗神经病变的发生。总之，该项目将定义化疗引起的疼痛的机制，确定新的近期治疗方案，并建立设计和证明后续临床试验所需的关键数据库。因此，该项目将提高生活质量，生存和恢复生产力，每年成千上万的患者受到这种神经病变的影响。

DESCRIPTION (provided by applicant): Painful neuropathy is the principal dose-limiting factor requiring discontinuation of chemotherapy with vincristine, taxol and cisplatin, the frontline chemotherapeutic drugs used for a multitude of tumors, including leukemia, lung, and breast cancers, those most common in Americans. Moreover, this pain is refractory to treatment and often persists in cancer survivors. The long-term goal of this project is to determine the mechanism of chemotherapy-induced pain and identify potential therapeutic interventions for its relief and prevention. Three hypotheses related to this goal will be tested in three specific aims that are composed of complementary studies in humans who have received or are undergoing chemotherapy with vincristine, taxol or cisplatin and in animals treated with the same compounds. Hypothesis 1: Vincristine, taxol and cisplatin have shared effects on primary afferent fiber function that contribute to neuropathic pain. This hypothesis will be tested in humans alone. Specific Aim 1.1: Primary afferent function will be tracked by quantitative sensory testing over time during chemotherapy in cancer patients. The results in patients who develop pain will be contrasted with those in normal volunteers and with data from patients who do not develop pain. Hypothesis 2: Vincristine, taxol and cisplatin have shared effects on pro-inflammatory cytokines that contribute to neuropathic pain. This hypothesis will be tested in humans and animals. Specific Aim 2.1: Blood serum levels of cytokines, quantitative sensory function and symptom assessments will be tracked over time in patients as they undergo chemotherapy. The results in patients who develop pain will be contrasted to normative controls and to patients who do not develop pain. Specific Aim 2.2: In animals, the expression of cytokines in blood serum, spinal cord, dorsal root ganglia, and plantar skin will be measured over time with chemotherapy. Hypothesis 3: Chemotherapy-induced neuropathy is produced by the action of proinflammatory cytokines in specific body compartments. This will be tested in animals alone. Specific Aim 3.1: Individual cytokines shown to be elevated by chemotherapy will be infused onto spinal cord, dorsal root ganglia and around nerve endings in skin to reproduce the behavioral signs of chemo-neuropathy. Specific Aim 3.2: Cytokine antagonists will be administered systemically and into local body compartments in parallel with the chemotherapeutic drugs to prevent the onset of chemo-neuropathy. In summary this project will define mechanisms of chemotherapy-induced pain, identify novel near-term treatment candidates, and establish the key databases needed to design and justify follow-up clinical trials. This project will therefore improve the quality of life, survival and return to productivity of hundreds of thousands of patients that are affected by this neuropathy each year.