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，是黑色素瘤发病机制、皮肤早衰和免疫抑制的重要因素。非黑色素瘤皮肤癌是迄今为止最常见的皮肤恶性肿瘤，对公共卫生和卫生保健支出产生巨大影响。人们一直在努力确定补充和替代药物，以防止紫外线辐射过度照射的不利生物效应。从绿茶中分离出的多酚组分（GTP）对光致癌和紫外线诱导的免疫抑制具有显著的化学预防作用。本提案中提出的研究是基于我们的观察，在小鼠中，局部或饮用水中给药GTP （d.w.）抑制uvb诱导的免疫反应抑制，这种抑制与紫外线辐射对IL-12产生的协同作用有关。由于已知IL-12可以逆转紫外线诱导的免疫抑制，这被认为是癌症诱导的危险因素，并且具有抗肿瘤活性，我们假设GTP至少在一定程度上通过增加小鼠中紫外线诱导的IL-12来介导其化学预防作用。我们提出以下具体目标，以验证在d.w.中给予小鼠GTP调节uvb诱导的免疫反应，并随后通过其诱导IL-12的能力至少部分地抑制光致癌作用的假设。为了验证这一假设，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标。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，(2)免疫抑制作用。这些研究还将探讨GTP是否对所有类型的皮肤肿瘤都同样有效。由于紫外线诱导的DNA损伤主要以环丁烷嘧啶二聚体的形式存在，是紫外线诱导免疫抑制和光致癌起始的重要分子触发因素，在Specific Aim-3中，我们将确定GTP治疗是否通过激活DNA修复酶来减少紫外线诱导的DNA损伤，以及IL-12是否参与这一过程。本研究的结果可能会产生新的知识，以确定绿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，通过使用绿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，全世界对绿茶作为人类癌症化学预防剂的兴趣正在增加，因为绿茶无毒，价格合理，受欢迎的饮料，对许多器官都有效。

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.