Role of beta-endorphin in cancer therapy induced fatigue

β-内啡肽在癌症治疗引起的疲劳中的作用

• 批准号: 8233976
• 负责人: DAVID E FISHER
• 金额: $ 35.36万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233976
• 关键词: Addictive Behavior; Adriamycin PFS; Affect; Anesthesiology; Animals; Apoptotic; Behavior; Behavioral; Biometry; Blood; Cancer Center; Cancer Patient; Cessation of life; Cleaved cell; Clinical Trials; Cutaneous; DNA Damage; Data; Dose; Electron Beam; Endorphins; Exhibits; Fatigue; Follow-Up Studies; Future; Human; Institutional Review Boards; Ionizing radiation; Life; Measurement; Measures; Mediating; Medical Oncology; Melanocyte stimulating hormone; Mental Depression; Monitor; Moods; Mus; Naloxone; Naltrexone; Narcotic Antagonists; Oncologic Nursing; Oncology Nurse; Opiates; Opioid Receptor; Pain; Pathway interactions; Patients; Peptides; Perception; Pharmaceutical Preparations; Phenotype; Pigmentation physiologic function; Plasma; Population Study; Pre-Clinical Model; Pro-Opiomelanocortin; Production; Quality of life; Questionnaires; Radiation; Radiation Oncology; Radiation Toxicity; Radiation therapy; Radiobiology; Rattus; Rodent; Role; Schedule; Self Assessment; Series; Severities; Signal Transduction; Simulate; Skin; Skin Pigmentation; Skin tanning; Specialist; Staging; Tail; Testing; The Sun; Toxic effect; Treatment Protocols; UV induced; UV induced DNA damage; Ultraviolet Rays; Vitamin D; Vitamin D Deficiency; base; beta-Endorphin; cancer radiation therapy; cancer therapy; chemotherapy; improved; instrument; irradiation; keratinocyte; malignant breast neoplasm; pre-clinical; prevent; prospective; public health relevance; response; sensor; therapeutic target; ultraviolet damage

DESCRIPTION (provided by applicant): Fatigue occurs in up to 80% of cancer patients undergoing radiation or chemotherapy and is significantly debilitating. Our lab studies skin signaling which mediates UV induced pigmentation. UV damages DNA in keratinocytes, thereby stabilizing p53 which stimulates expression of pro-opiomelanocortin (POMC). In turn, POMC is cleaved into several peptides, one of which, Melanocyte Stimulating Hormone, activates pigmentation. Another POMC derived peptide is 2-endorphin. We have observed elevations in systemic blood levels of 2-endorphin following repeated low-dose UV radiation. Multiple studies suggest that UV may trigger opiate-like addictive behaviors, which are likely mediated by this UV-POMC-2endorphin axis. We believe the origins of this behavioral linkage may relate to evolutionary advantages of sun-seeking behaviors to maintain UV derived cutaneous vitamin D synthesis. Since control of this pathway is exerted by p53 (DNA damage sensor), we tested whether non-UV DNA damage triggers, especially ionizing radiation or certain chemotherapeutics, may also trigger 2-endorphin synthesis and found that they do. Fatigue is a prominent opiate phenotype, and one which accompanies the majority of cancer patients undergoing therapies which are known to potently induce p53. We observed elevations in blood 2-endorphin following either large single doses or repeated fractionated doses of either UV or ionizing radiation, as well as adriamycin in rodents. As with tanning/pigmentation, this 2-endorphin response is absent in p53-/- mice. Using fractionated tail ionizing irradiation (simulating cancer radiation therapy) we observed elevations in blood 2-endorphin after several weeks. Quantitative rat actimetry measurements revealed major locomotor depression, indicative of severe fatigue, which precisely correlated temporally with 2-endorphin blood elevations. Most importantly, the locomotor/fatigue changes were rapidly and fully reversed by treatment with the 5-opiate receptor antagonist naloxone. A role for 2-endorphin in human radiation fatigue would be particularly important because drugs which modulate this pathway are readily available to apply to patients. We propose to expand these studies preclinically and clinically in the following Specific Aims: 1) carry out a prospective clinical trial to examine blood 2-endorphin levels together with self-assessments of fatigue and other opiate-related behavioral phenotypes using validated questionnaire instruments in humans undergoing chemotherapy and/or radiation therapy for breast cancer, 2) dissect parameters of this pathway pre-clinically, specifically testing a) radiation dose-response, b) relationship between fatigue and radiation skin toxicity, c) electron beam radiation, d), adriamycin induced fatigue (naloxone reversibility), e) crosstalk/impact of vitamin D deficiency, and f) optimization of naltrexone schedule/dosing. These mechanism-based studies may set the stage for rapid application of opiate pathway modulation using existing drugs, as a targeted therapeutic approach for this major quality of life challenge in cancer patients. PUBLIC HEALTH RELEVANCE: We recently found that sun/UV damage to skin stimulates production of 2- endorphin which is addictive. The same DNA damage pathway is triggered by chemotherapy or ionizing radiation, which was seen to produce major fatigue in rats that was fully reversed by the opiate antagonist naloxone. This 2-endorphin - fatigue axis offers a profound treatment opportunity to improve quality of life in cancer patients, which we will examine in a human clinical trial and a series of preclinical animal studies.

描述（由申请人提供）：高达80%的接受放疗或化疗的癌症患者会出现疲劳，并显着衰弱。我们的实验室研究介导紫外线诱导色素沉着的皮肤信号。紫外线损伤角质形成细胞中的DNA，从而稳定刺激阿黑皮素原（POMC）表达的p53。反过来，POMC被切割成几种肽，其中之一，黑素细胞刺激激素，激活色素沉着。另一种POMC衍生肽是2-内啡肽。我们已经观察到，在反复低剂量紫外线照射后，2-内啡肽的全身血液水平升高。多项研究表明，紫外线可能会引发阿片类成瘾行为，这可能是由这个UV-POMC-2内啡肽轴介导的。我们相信这种行为联系的起源可能与寻求阳光的行为的进化优势有关，以维持紫外线衍生的皮肤维生素D合成。由于这一途径的控制是由p53（DNA损伤传感器）发挥作用，我们测试了非紫外线DNA损伤触发器，特别是电离辐射或某些化疗药物，是否也可能触发2-内啡肽的合成，并发现它们确实如此。疲劳是一种突出的阿片类药物表型，并且伴随着大多数接受已知有效诱导p53的治疗的癌症患者。我们观察到血液中的2-内啡肽升高后，无论是大剂量或重复分次剂量的紫外线或电离辐射，以及阿霉素在啮齿动物。与晒黑/色素沉着一样，这种2-内啡肽反应在p53-/-小鼠中不存在。使用分次尾部电离辐射（模拟癌症放射治疗），我们观察到血液2-内啡肽升高数周后。定量大鼠活动测量显示严重的运动抑制，表明严重疲劳，这与2-内啡肽血液升高在时间上精确相关。最重要的是，运动/疲劳的变化迅速和完全逆转与5-阿片受体拮抗剂纳洛酮治疗。2-内啡肽在人类辐射疲劳中的作用将是特别重要的，因为调节该途径的药物可容易地应用于患者。我们建议在临床前和临床上扩展这些研究，具体目的如下：1）进行前瞻性临床试验，以在接受乳腺癌化疗和/或放疗的人中使用经验证的问卷工具检查血液2-内啡肽水平以及疲劳和其他阿片类药物相关行为表型的自我评估，2）在临床前剖析该途径的参数，具体测试a）辐射剂量-反应，B）疲劳和辐射皮肤毒性之间的关系，c）电子束辐射，d）阿霉素诱导的疲劳（纳洛酮可逆性），e）维生素D缺乏的串扰/影响，和f）纳洛酮时间表/剂量的优化。这些基于机制的研究可能为使用现有药物快速应用阿片途径调节奠定基础，作为癌症患者这一主要生活质量挑战的靶向治疗方法。 公共卫生相关性：我们最近发现阳光/紫外线对皮肤的损伤会刺激2-内啡肽的产生，这会让人上瘾。化疗或电离辐射也会触发相同的DNA损伤途径，这在大鼠中引起了严重的疲劳，而阿片拮抗剂纳洛酮则完全逆转了这种疲劳。这个2-内啡肽-疲劳轴提供了一个深刻的治疗机会，以改善癌症患者的生活质量，我们将在人体临床试验和一系列临床前动物研究中进行研究。