Mechanisms of Cancer Therapy-Induced Pain

描述(申请人提供)：痛性神经病是需要停止长春新碱、紫杉醇和顺铂化疗的主要剂量限制因素，长春新碱、紫杉醇和顺铂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，这种疼痛难以治疗，通常会在癌症幸存者身上持续存在。该项目的长期目标是确定化疗引起的疼痛的机制，并确定缓解和预防疼痛的潜在治疗干预措施。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，这三个目标由已经接受或正在接受长春新碱、紫杉醇或顺铂化疗的人类以及接受相同化合物治疗的动物的补充性研究组成。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影响，从而导致神经病理性疼痛。这一假设将只在人类身上进行测试。具体目标1.1：在癌症患者化疗期间，将通过定量感觉测试来跟踪初级传入功能。出现疼痛的患者的结果将与正常志愿者的结果以及不出现疼痛的患者的数据进行对比。假设2：长春新碱、紫杉醇和顺铂对促进神经病理性疼痛的促炎细胞因子有共同作用。这一假设将在人类和动物身上进行检验。具体目标2.1：将跟踪患者在接受化疗期间的血清细胞因子水平、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组和不出现疼痛的患者进行对比。具体目的2.2：在动物中，随着化疗时间的推移，细胞因子在血清、脊髓、背根神经节和足底皮肤中的表达将被测量。假设3：化疗引起的神经病是由体内特定区域的促炎细胞因子作用产生的。这将仅在动物身上进行测试。具体目标3.1：将化疗后升高的单个细胞因子注入脊髓、背根神经节和皮肤神经末梢周围，以重现化疗神经病的行为迹象。具体目标3.2：细胞因子拮抗剂将在化疗药物的同时，系统地和局部体内隔室给药，以防止化学神经病的发生。总而言之，该项目将确定化疗引起疼痛的机制，确定新的近期治疗候选者，并建立设计和证明后续临床试验所需的关键数据库。因此，该项目将改善每年数十万受这种神经疾病影响的患者的生活质量、存活率和恢复生产力。

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.