Psoralens and melanoma

补骨脂素和黑色素瘤

• 批准号: 8957580
• 负责人: EUNYOUNG CHO
• 金额: $ 22.19万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8957580
• 关键词: 5-methoxypsoralen; 8-MOP; Acute; Address; Archives; Biological Assay; Blood; Botanicals; Breslow Thickness; Characteristics; Citrus Fruit; Cohort Studies; Consumption; Cutaneous Melanoma; DNA; Data; Databases; Diagnostic; Diet; Dietary intake; Disease Outcome; Drug Interactions; Drug Metabolic Detoxication; Epidemiologic Studies; Epidemiology; Evaluation; Ficusin; Food; Frequencies; Fruit; Furanocoumarins; Future; Grapefruit; Guidelines; Health; Health Professional; Human; Human body; Incidence; Individual; Induced Mutation; Intake; Investigation; Laboratories; Lead; Lesion; Life Style; Location; Malignant Neoplasms; Measures; Metabolic; Methoxsalen; Nurses' Health Study; Oral; Parents; Participant; Patients; Persons; Photons; Phototoxicity; Pilot Projects; Plasma; Positioning Attribute; Process; Psoralens; Psoriasis; Public Health; Questionnaires; Reproducibility; Retrospective Studies; Risk; Role; Route; Sampling; Skin; Skin Cancer; Time; UVA Light Therapy; Ultraviolet A radiation; Urine; Vitiligo; Woman; cancer prevention; carcinogenesis; cohort; experience; follow-up; fruits and vegetables; genetic risk factor; melanoma; men; phytoalexin; phytoalexins; prospective; skin disorder; tumor; urinary

 DESCRIPTION (provided by applicant): Incidence of cutaneous melanoma has been increasing. We recently found that intake of citrus fruits, especially grapefruit, was associated with increased risk of developing melanoma and believe that psoralens in citrus fruits may be responsible for the association. An oral 8-methoxy psoralen (8-MOP; methoxsalen) in combination with ultraviolet-A radiation (Psoralen and UVA Light [PUVA] therapy) is used to treat skin disorders and found to be associated with increased incidence of melanoma. Psoralens are a group of naturally occurring linear furocoumarins (furanocoumarins) in fruits and vegetables and are potentially phototoxic and photocarcinogenic; they intercalate DNA and photochemically induce mutations. The levels of furocoumarins present in our diets, while normally well below levels that would cause evident acute phototoxicity, do cause pharmacologically relevant drug interactions, known as the `grapefruit effect'. Furthermore, there are no efficient routes for the metabolic detoxification of psoralens in humans. Consequently, low levels of psoralens, which are not completely excreted, may occur in our skin awaiting suitable photon interactions to create mutational lesions potentially resulting in melanoma or other skin cancers. Citrus fruit consumption has increased substantially in the US. However, there is a lack of epidemiological data on dietary psoralen intake in relation to melanoma risk because food composition database for dietary psoralens are not available. Data are lacking on blood and urine psoralen levels in humans. Therefore, in this proposal, we plan to capitalize on existing dietary data collected in large cohort studies (where the positive association between citrus fruit intake and melanoma risk was found) and propose to construct a food composition database on dietary psoralens through direct assessment of several common psoralens in psoralen-rich foods including citrus fruit items and to evaluate dietary psoralen intake in relation to melanoma risk with at least 1,000 melanoma cases. We also propose to conduct a pilot study to investigate whether we can detect these psoralens in archived blood and urine samples of large cohort studies and to assess laboratory variability, stability due to delays in processing, and within-person variability of the blood and urinary psoralens. We are uniquely positioned to most efficiently address the hypotheses. The results of the investigation will pave the way for future studies that will capitalize on these findings and cn lead to studies of plasma or urine psoralen levels to unveil the roles of naturally occurring psoralens in carcinogenesis. Because dietary guidelines for cancer prevention encourage consumption of fruits and vegetables, clarification of the effect of naturally occurring psoralens on carcinogenesis has public health implications as we have experienced through the findings of `grapefruit effect'.

 描述（由申请人提供）：皮肤黑色素瘤的发病率一直在增加。我们最近发现，摄入柑橘类水果，特别是葡萄柚，与患黑色素瘤的风险增加有关，并认为柑橘类水果中的多酚可能是导致这种关联的原因。口服8-甲氧基补骨脂素（8-MOP;甲氧沙林）与紫外线-A辐射（补骨脂素和UVA光[PUVA]疗法）联合用于治疗皮肤病，并发现与黑素瘤发病率增加有关。香豆素是水果和蔬菜中天然存在的一组线性呋喃香豆素（呋喃香豆素），具有潜在的光毒性和光致癌性;它们嵌入DNA并光化学诱导突变。我们饮食中存在的呋喃香豆素水平，虽然通常远低于引起明显急性光毒性的水平，但确实会引起与药物相关的相互作用，称为“葡萄柚效应”。此外，没有有效的途径代谢解毒的peptiens在人类。因此，未完全排出的低水平的peptiens可能会出现在我们的皮肤中，等待适当的光子相互作用以产生可能导致黑色素瘤或其他皮肤癌的突变病变。在美国，柑橘类水果的消费量大幅增加。然而，由于没有膳食中摄入的补骨脂素的食物成分数据库，因此缺乏关于膳食中摄入补骨脂素与黑色素瘤风险之间关系的流行病学数据。目前还缺乏关于人体血液和尿液中peptide水平的数据。因此，在本提案中，我们计划利用大型队列研究中收集的现有饮食数据，（研究发现柑橘类水果的摄入量与患黑色素瘤的风险呈正相关），并建议通过直接评估常见的柑橘类水果中的几种柑橘类水果，建立一个关于柑橘类水果的食物成分数据库，包括柑橘类水果在内的丰富食物，并评估至少1,000例黑色素瘤病例中膳食中的多酚摄入量与黑色素瘤风险的关系。我们还建议进行一项试点研究，以调查我们是否可以检测到这些peptides在存档的血液和尿液样本的大型队列研究，并评估实验室的变异性，稳定性，由于延迟处理，以及血液和尿液peptides的人内变异性。我们处于独特的地位，可以最有效地解决这些假设。调查结果将为未来的研究铺平道路，这些研究将利用这些发现，并可能导致血浆或尿液中peptides水平的研究，以揭示自然发生的peptides在致癌作用中的作用。由于预防癌症的饮食指南鼓励食用水果和蔬菜，澄清天然存在的peptiens对致癌作用的影响具有公共卫生意义，正如我们通过“葡萄柚效应”的发现所经历的那样。