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: 8105969
• 负责人: DAVID E FISHER
• 金额: $ 35.4万
• 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/8105969
• 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; 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(申请人提供)：在接受放射或化疗的癌症患者中，高达80%会出现疲劳，并使人严重虚弱。我们的实验室研究皮肤信号，它介导了紫外线诱导的色素沉着。紫外线损伤角质形成细胞中的DNA，从而稳定P53，从而刺激前阿片黑素皮质素(POMC)的表达。反过来，POMC被裂解成几个肽，其中之一，黑素细胞刺激素，激活色素沉着。POMC衍生的另一种多肽是2-内啡肽。我们观察到反复低剂量紫外线照射后全身血液中2-内啡肽水平的升高。多项研究表明，紫外线可能触发阿片类成瘾行为，这可能是由UV-POMC-2内啡素轴介导的。我们认为，这种行为关联的起源可能与寻找太阳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)实施的，我们测试了非紫外线DNA损伤触发因素，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，并发现确实如此。疲劳是一种突出的阿片类药物表型，大多数接受治疗的癌症患者都会出现疲劳，已知这些治疗会有效地诱导p53基因的产生。我们观察到，在大剂量单次紫外线或电离辐射以及阿霉素照射后，啮齿类动物的血液中2-内啡肽水平升高。与晒黑/色素沉着一样，这种2-内啡肽反应在P53-/-小鼠中缺失。采用分次尾部电离辐射(模拟癌症放射治疗)，观察几周后血中2-内啡肽的升高。定量的大鼠运动测量显示出主要的运动抑制，这表明严重的疲劳，这与2-内啡肽的血液升高在时间上精确地相关。最重要的是，5-阿片受体拮抗剂纳洛酮可迅速完全逆转运动/疲劳的变化。2-内啡肽在人类辐射疲劳中的作用将特别重要，因为调节这一途径的药物很容易应用于患者。我们建议在临床前和临床上扩大这些研究的具体目标：1)开展一项前瞻性临床试验，使用经过验证的问卷调查工具，检测接受乳腺癌化疗和/或放射治疗的人的血液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)临床前剖析这一途径的参数，具体测试a)辐射剂量-反应，b)疲劳与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，以及f)纳曲酮时间表/剂量的优化。这些基于机制的研究可能为利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有针对性的治疗方法。 与公共健康相关：我们最近发现，阳光/紫外线对皮肤的伤害会刺激2-内啡肽的产生，这会使人上瘾。化疗或电离辐射也会触发同样的DNA损伤途径，这被认为会导致大鼠的严重疲劳，而阿片类拮抗剂纳洛酮可以完全逆转这一现象。这种2-内啡肽-疲劳轴为改善癌症患者的生活质量提供了一个深刻的治疗机会，我们将在人类临床试验和一系列临床前动物研究中对此进行研究。