Importance of Gender in the Chemoprevention of UV induced Skin Cancer

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，在美国每年发现超过100万例新病例。事实上，更多的美国人将被诊断出患有某种形式的皮肤癌，而不是所有其他癌症的总和。流行病学研究表明，NMSC的发展存在性别差异，男性患NMSC的可能性一般是女性的两倍，患鳞状细胞癌的可能性是女性的三倍。这种差异归因于生活方式的选择，因为男性历来从事需要更多时间在阳光下的职业，并且不太可能使用防晒用品。然而，没有研究确定当男性和女性接受相同的累积紫外线照射时，皮肤肿瘤发展是否存在性别差异。我们实验室最近的研究表明，紫外线在男性和女性皮肤中发挥其破坏作用的途径是不一样的，阻断男性皮肤中紫外线诱导的炎症可能不如女性皮肤中有效地减少肿瘤的发展。拟议研究的主要目标是确定男性和女性皮肤UVB反应的潜在机制差异，并确定UV诱导的SCC的启动，促进和进展的性别差异。提出了两个具体的目标，以测试的假设，即降低抗氧化剂活性水平，增加活性氧（ROS）的生产和增加氧化DNA损伤的男性皮肤不仅影响急性皮肤反应UVB暴露，但也有助于观察到的性别差异的发展NMSC。特定目标1的研究将确定抗氧化剂和炎症产生的活性氧对未辐照皮肤中DNA损伤的不同贡献，以及在雄性和雌性Skh-1小鼠皮肤中急性UVB诱导的炎症反应期间。特定目标2中的研究旨在确定抗氧化剂（维生素E）、抗炎药（celebrex）、天然抗氧化剂/抗炎剂（黑树莓提取物）或两者组合局部治疗对雄性与雌性Skh-1小鼠中UV诱导的肿瘤发生、促进和进展的差异化学预防作用。更清楚地了解男性和女性皮肤的差异最终将有助于制定更有针对性的预防和治疗策略。

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.