Mechanisms of Cancer Therapy-Induced Pain

癌症治疗引起的疼痛的机制

基本信息

批准号：
7561642
负责人：
Patrick M Dougherty
金额：
$ 35.63万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-15 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7561642
关键词：
Abbreviations Accounting Affect American Animals Axonal Transport Back Behavioral Cancer Patient Cancer Survivor Cells Cisplatin Clinical Research Clinical Trials Complement DNA Data Databases Development Disease Distress Dose Dose-Limiting Drops Drug usage Effectiveness Enzyme-Linked Immunosorbent Assay Fiber Follow-Up Studies Generations Goals Granulocyte-Macrophage Colony-Stimulating Factor Hand High Dose Chemotherapy Human Hyperalgesia Immune Impairment In Vitro Individual Inflammatory Interferons Interleukins Kineret Lipopolysaccharides Literature Lung Lymphocyte Malignant Neoplasms Measurement Measures Mechanics Microtubules Minocycline Modeling Molecular Monocyte Chemoattractant Proteins NF-kappa B Nerve Nerve Endings Nerve Growth Factors Nervous system structure Neuroglia Neurologic Neurons Neuropathy Neurophysiology - biologic function Neurotrophin 3 Numbness Paclitaxel Pain Pathogenesis Patients Pharmaceutical Preparations Play Prevention Production Productivity Provider Psychophysiology Publishing Quality of life Rattus Refractory Rehabilitation therapy Research Personnel Role Sensory Serum Skin Somatomedins Source Spinal Spinal Cord Spinal Ganglia Symptoms Testing Text Thalidomide Therapeutic Intervention Time Tumor Burden Tumor Necrosis Factor-alpha Tumor Necrosis Factors Vincristine animal data base cancer care cancer cell cancer therapy cell type chemotherapy chemotherapy induced neuropathy cytokine design dorsal horn follow-up improved in vivo indexing inflammatory pain leukemia malignant breast neoplasm novel painful neuropathy prevent research study response species difference theories tumor volunteer

项目摘要

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.

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，需要停止长春新碱、紫杉醇和顺铂化疗，这些一线化疗药物用于治疗多种肿瘤，包括白血病、肺癌和乳腺癌，这些最常见的肿瘤在美国人中。此外，这种疼痛难以治疗，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，并确定缓解和预防疼痛的潜在治疗干预措施。与该目标相关的三个假设将在三个具体目标中进行测试，这些目标由对已接受或正在接受长春新碱、紫杉醇或顺铂化疗的人类以及用相同化合物治疗的动物的补充研究组成。假设 1：长春新碱、紫杉醇和顺铂对导致神经性疼痛的初级传入纤维功能有共同的影响。该假设将仅在人类身上进行测试。具体目标 1.1：将通过癌症患者化疗期间随时间的定量感觉测试来跟踪主要传入功能。出现疼痛的患者的结果将与正常志愿者的结果以及未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具有共同作用。该假设将在人类和动物身上进行测试。具体目标 2.1：随着时间的推移，将跟踪接受化疗的患者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以及未出现疼痛的患者进行对比。具体目标 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特定身体部位促炎细胞因子的作用产生的。这将仅在动物身上进行测试。具体目标 3.1：化疗后显示升高的个体细胞因子将被注入脊髓、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体征。具体目标 3.2：细胞因子拮抗剂将与化疗药物同时全身给药并进入局部身体部位，以预防化疗神经病的发生。总之，该项目将定义化疗引起的疼痛的机制，确定新的近期候选治疗方案，并建立设计和证明后续临床试验所需的关键数据库。因此，该项目将提高每年数十万受这种神经病影响的患者的生活质量、生存率并恢复其生产力。