Prevention of skin cancer by green tea polyphenols

描述（由申请人提供）：长期暴露于太阳紫外线辐射是美国每年超过100万例新发非黑色素瘤皮肤癌的主要病因，并且是黑色素瘤、皮肤过早老化和免疫抑制发病机制的重要因素。非黑色素瘤皮肤癌是迄今为止最常见的皮肤恶性肿瘤，对公共卫生和医疗保健支出有巨大影响。目前正在作出协调一致的努力，以确定能够防止紫外线辐射过度造成的不良生物影响的补充和替代药物。从绿色茶中提取的多酚类化合物（GTP）具有显著的光致癌作用和紫外线诱导的免疫抑制作用。本提案中提出的研究是基于我们的观察，在小鼠中，局部或在饮用水（d.w.）抑制UVB诱导的免疫应答抑制，并且这种抑制与UV辐射对IL-12产生的协同效应有关。由于已知IL-12可逆转UV诱导的免疫抑制，这被认为是癌症诱导的风险因素，并且具有抗肿瘤活性，因此我们推测GTP至少部分地通过增强小鼠中UV诱导的IL-12介导其化学预防作用。我们提出了以下具体目标来检验d.w.中给出的GTP的假设。调节UVB诱导的免疫反应，并随后至少部分地通过其诱导IL-12的能力抑制光致癌作用。为了检验该假设，在IL-12敲除及其野生型对应物的小鼠模型中提出了以下特定目的。我们将确定IL-12是否参与GTP对UVB诱导的化学预防作用：（1）光致癌作用，和（2）免疫抑制。这些研究还将解决GTP是否对所有类型的皮肤肿瘤同样有效。由于UV诱导的DNA损伤（主要以环丁烷嘧啶二聚体的形式）是UV诱导的免疫抑制和光致癌作用启动的重要分子触发因素，因此在Specific Aim-3中，我们将确定GTP处理是否通过激活DNA修复酶减少UV诱导的DNA损伤，以及IL-12是否参与此过程。从这项研究中获得的结果可能导致新的知识的产生，以确定绿色茶多酚发挥其皮肤癌化学预防作用的作用机制。这将导致开发新的方法和免疫调节策略，通过采用绿色茶中的多酚作为补充和替代药物来预防太阳紫外线辐射引起的人类皮肤癌。重要的是，全世界对绿色茶作为人类癌症化学预防剂的兴趣正在增加，因为它是无毒的，负担得起的，受欢迎的饮料，并且在广泛的器官中有效。

DESCRIPTION (provided by applicant): Chronic exposure to solar UV radiation is the major etiological agent for over one million new non-melanoma skin cancers in the United States each year and is an important factor in the pathogenesis of melanoma, premature aging of the skin and immunosuppression. Non-melanoma skin cancer is by far the most common cutaneous malignancy and has a tremendous impact on public health and health care expenditures. There has been a concerted effort to identify complementary and alternative medicine that will protect against the adverse biological effects of UV radiation overexposure. A polyphenolic fraction isolated from green tea (GTP) has remarkable chemopreventive effects against photocarcinogenesis and UV-induced immunosuppression. The proposed studies in this proposal are based on our observations that, in mice, administration of GTP either topically or in drinking water (d.w.) inhibits UVB-induced suppression of immune responses and this inhibition was associated with the synergistic effect on IL-12 production with UV radiation. As IL-12 is known to reverse UV-induced immunosuppression, which is considered to be a risk factor for cancer induction, and has anti-tumor activity, we postulate that GTP mediates its chemopreventive effects, at least in part, through the augmentation of UV-induced IL-12 in mice. We propose the following specific aims to test the hypothesis that GTP given in d.w. to mice modulates UVB-induced immunological responses and subsequently inhibits photocarcinogenesis, at least in part, through its ability to induce IL-12. To test this hypothesis the following Specific Aims are proposed in a mouse model of IL-12 knockouts and their wild type counterparts. We will determine whether IL-12 is involved in the chemopreventive effects of GTP on UVB-induced: (1) photocarcinogenesis, and (2) immunosuppression. These studies also will address whether GTP is equally effective against all types of skin tumors. As UV-induced DNA damage, predominantly in the form of cyclobutane pyrimidine dimers, is an important molecular trigger of UV-induced immunosuppression and initiation of photocarcinogenesis, in Specific Aim-3, we will determine whether GTP treatment reduces UV-induced DNA damage through activation of DNA repair enzymes and if IL-12 is involved in this process. The results obtained from this study may lead to the generation of new knowledge to identify the mechanism of action by which green tea polyphenols exert their skin cancer chemopreventive effects. This will lead to the development of new methods and immunomodulatory strategies for the prevention of solar UV radiation-induced skin cancer in humans by employing polyphenols from green tea as a complementary and alternative medicine. Importantly, worldwide interest in green tea as a cancer chemopreventive agent for humans is increasing because it is non-toxic, affordable, popular beverage and is effective in a wide range of organs.