Importance of Gender in the Chemoprevention of UV induced Skin Cancer

性别在紫外线诱发皮肤癌化学预防中的重要性

• 批准号: 7994870
• 负责人: TATIANA M OBERYSZYN
• 金额: $ 30.19万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7994870
• 关键词: Acute; American; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Basal cell carcinoma; Biological; Chemoprevention; Chemopreventive Agent; Chronic; Cutaneous; DNA Damage; Development; Diagnosis; Dose; Environmental Carcinogens; Epidemiologic Studies; Exhibits; Exposure to; Female; Gender; Goals; Health; Hour; Human; Inbred HRS Mice; Inflammation; Inflammatory Response; Laboratories; Lesion; Life Style; Longitudinal Studies; Malignant Neoplasms; Mus; Pathway interactions; Pharmaceutical Preparations; Prevention; Prevention strategy; Production; Raspberries; Reactive Oxygen Species; Reporting; Sex Bias; Sex Characteristics; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Skin Neoplasms; Squamous cell carcinoma; Testing; The Sun; Time; Topical application; Tumor Promotion; UV Radiation Exposure; UV induced; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; United States; Vitamin E; Woman; Work; celecoxib; cyclooxygenase 2; design; inhibitor/antagonist; male; men; mouse model; oxidative DNA damage; prevent; response; sun protection; treatment strategy; tumor; tumor growth; tumor initiation; tumor progression

DESCRIPTION (provided by applicant): Non-melanoma skin cancers (NMSC) are the most common form of cancer in humans, with over 1 million new cases identified in the United States each year. In fact, more Americans will be diagnosed with some form of skin cancer than all other cancers combined. Epidemiological studies have shown that there are gender differences in the development of NMSC, with men being as twice as likely to NMSC in general and three times as likely to develop squamous cell carcinomas as women. This disparity has been attributed to lifestyle choices, since males historically have had professions requiring more time out in the sun and are less likely to use sun protection. However, no studies had determined if gender differences in skin tumor development occur when males and females receive equivalent cumulative UV exposure. Recent studies from our laboratory suggest that the pathways by which UV exerts its damaging effects in male and female skin are not the same and that blocking UV-induced inflammation in male skin may not be as effective in decreasing tumor development as in female skin. The primary goals of the proposed studies are to determine the underlying mechanistic differences in the UVB response of male and female skin and to identify differences between the genders in initiation, promotion and progression of UV-induced SCC. Two specific aims are proposed to test the hypothesis that decreased levels of antioxidant activity, increased reactive oxygen species (ROS) production and increased oxidative DNA damage in male skin not only influence the acute cutaneous response to UVB exposure but also contribute to the observed gender disparity in the development of NMSC. Studies in Specific Aim 1 will determine the differential contribution of antioxidants and inflammation generated reactive oxygen species to DNA damage in unirradiated skin and during an acute UVB-induced inflammatory response in male and female Skh-1 murine skin. Studies in Specific Aim 2 are designed to determine the differential chemopreventive effects of topical treatment with an antioxidant (vitamin E), an anti-inflammatory drug (celebrex), a natural antioxidant/anti-inflammatory agent (Black Raspberry extract) or a combination of the two on UV induced tumor initiation, promotion and progression in male vs. female Skh-1 mice. A clearer understanding of the differences in the skin of males and females will ultimately allow for the development of more appropriately targeted prevention and treatment strategies. PUBLIC HEALTH RELEVANCE: Exposure to Ultraviolet light is believed to be the single most important etiological factor in the development on skin cancer. Epidemiological studies have shown that there are gender differences in the development of nonmelanoma skin cancer (NMSC) with men being as twice as likely to develop NMSC and three times as likely to develop squamous cell carcinoma as women. This disparity has been attributed to lifestyle choices, since males historically have had professions requiring more time out in the sun and are less likely to use sun protection. Recent studies from our laboratory using the Skh-1 mouse model have demonstrated inherent biological differences in the skin of males and females. The studies in the current proposal are designed to understand the differential response of male and female skin to both acute and chronic ultraviolet light exposure. A clearer understanding of the differences in the skin of males and females will ultimately allow for the development of more appropriately targeted prevention and treatment strategies for this most common form of cancer in humans.

描述（由申请人提供）： 非黑色素瘤皮肤癌（NMSC）是人类最常见的癌症形式，每年在美国确定超过100万例新病例。实际上，与所有其他癌症的综合相比，将被诊断出某种形式的皮肤癌。流行病学研究表明，NMSC的发展存在性别差异，男性通常是NMSC的可能性是NMSC的两倍，而发展鳞状细胞癌的可能性是女性的三倍。这种差距归因于生活方式的选择，因为从历史上看，男性在阳光下需要更多的时间，并且不太可能使用防晒。但是，没有研究确定当男性和女性接受等效累积紫外线暴露时，皮肤肿瘤发育的性别差异是否发生。我们实验室的最新研究表明，紫外线在雄性和女性皮肤中施加破坏性作用的途径并不相同，并且阻塞紫外线诱导的雄性皮肤炎症在降低肿瘤发育方面可能没有像女性皮肤那样有效。拟议研究的主要目标是确定男性和女性皮肤UVB反应的潜在机理差异，并确定性别在开始，促进和进展的UV诱导的SCC方面的差异。提出了两个具体的目的来检验以下假设：抗氧化活性水平降低，活性氧（ROS）产生增加以及雄性皮肤中氧化性DNA损伤的增加不仅影响对UVB暴露的急性皮肤反应，还会导致NMSC发展中观察到的性别差异。在特定目标1中的研究将确定抗氧化剂和炎症的差异贡献产生活性氧对未辐照的皮肤中的DNA损伤以及在急性UVB诱导的雄性和雌性SKH-1鼠皮肤的炎症反应中的差异贡献。特定目标2中的研究旨在确定用抗氧化剂（维生素E），一种抗炎药（Celebrex），一种天然抗氧化剂/抗炎药（黑色覆盆子提取物）或两者对UV诱导的肿瘤促进，男性促进和女性进展的差异化学预防作用，一种抗炎药（Celebrex），一种天然的抗氧化剂/抗炎药（黑色覆盆子提取物）或两者的组合。对男性和女性皮肤差异的更清晰了解最终将允许发展更适当的预防和治疗策略。公共卫生相关性：据信暴露于紫外线是皮肤癌发育中最重要的病因。流行病学研究表明，非黑色素瘤皮肤癌（NMSC）的发展存在性别差异，男性发展NMSC的可能性是女性的可能性两倍，而发展鳞状细胞癌的可能性是女性的两倍。这种差距归因于生活方式的选择，因为从历史上看，男性在阳光下需要更多的时间，并且不太可能使用防晒。我们实验室使用SKH-1小鼠模型的最新研究表明，男性和女性的皮肤上存在固有的生物学差异。当前提案中的研究旨在了解雄性和女性皮肤对急性和慢性紫外线暴露的差异反应。对男性和女性皮肤的差异的更清晰了解最终将允许为人类这种最常见的癌症形式的更适当的靶向预防和治疗策略发展。