Combined Natural Inhibitors in Skin Cancer Prevention

联合天然抑制剂预防皮肤癌

• 批准号: 6929349
• 负责人: THOMAS J SLAGA
• 金额: $ 36.5万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929349
• 关键词: alternative medicine; antineoplastics; biological products; cancer prevention; carcinogenesis inhibitor; carotenoids; chemical carcinogenesis; chemoprevention; dietary constituent; dimethylbenzanthracene; laboratory mouse; light adverse effect; nutrient drug interaction; nutrition aspect of cancer; nutrition related tag; phorbols; plant extracts; radiation carcinogenesis; skin neoplasms; topical drug application; ultraviolet radiation

DESCRIPTION (provided by applicant): The overall goal of this proposal is to determine the mechanism(s) of synergistic action of the natural source compounds, known to inhibit one or more stages of skin carcinogenesis, i.e., initiation and promotion/progression. Our hypothesis is that concurrent topical and systemic (i.e., dietary) treatment with selected natural source inhibitors of different stages of skin carcinogenesis result in synergistic effects leading to more efficient prevention of skin cancer. The inhibitors to be tested include ellagic acid, proanthocyanidin B-2-gallate, N-acetylcysteine, calcium D-glucarate, lycopene, ursolic acid from rosemary extract, and resveratrol. We propose to initially utilize a number of very predictive short-term in vitro and in vivo tests in order to identify the mechanism(s) and to differentiate the potencies of selected inhibitors at various concentrations under standard conditions. The most effective compounds will then be studied in long-term tumor experiments utilizing a 7,12-dimethylbenz[a]anthracene (DMBA)-initiated, 12-O-tetradecanoylphorbol-13-acetate (TPA)- promoted multistage carcinogenesis model in SENCAR mice and an ultraviolet light (UV)-initiated, TPA-promoted multistage carcinogenesis model in SKH-1 mice. Finally, combinations of the best anti-initiating and anti-tumor promoting agents will be tested in the DMBA-initiated, TPA-promoted skin carcinogenesis model in SENCAR mice as well as in the UV-initiated, TPA-promoted skin carcinogenesis model in SKH-1 mice. The following Specific Aims will be studied: (i) identification, using various very predictive short-term in vitro and in vivo tests, including the DMBA-induced inflammatory-hyperplasia assay in SENCAR mice and the UV-induced erythema-hyperplasia assay in SKH-1 mice, the most promising mechanisms of anti-initiation and anti-tumor promotion as well as the most effective natural source inhibitors and their delivery means, i.e., topical vs. systemic (dietary); (ii) analysis of the long-term anti-initiation and antitumor promoting effects of the selected, promising natural source inhibitors using the DMBA-initiated, TPA-promoted multistage skin carcinogenesis model in SENCAR mice to better understand their mechanism(s) of action and predict their performance in the following combination studies; (iii) studying the long-term inhibitory effects of the best anti-initiators and anti-tumor promoters identified in Aims 1 and 2, on UV-initiated, TPA-promoted multistage skin carcinogenesis in SKH-1 mice, in order to establish a bridge between the chemically induced and UV-induced mouse skin carcinogenesis data bases; (iv) examining how various combinations of mechanistically different anti-initiators and antitumor promoting agents and also how various combinations of their delivery means, i.e., topical vs. systemic (dietary), inhibit DMBA-initiated, TPA-promoted skin carcinogenesis in SENCAR mice as well as UV-initiated, TPA-promoted skin carcinogenesis in SKH-1 mice, with the view of discovering the most pronounced synergistic effects of the selected natural source inhibitors.

描述（由申请人提供）：该提案的总体目标是确定天然源化合物的协同作用的机制，已知可以抑制一个或多个皮肤癌变阶段，即启动和促进/进展。我们的假设是，与某些天然源抑制剂的同时局部和系统性（即饮食）治疗不同的皮肤致癌阶段会导致协同作用，从而更有效地预防皮肤癌。要测试的抑制剂包括椭圆酸，原蛋白素B-2-甘酸酯，N-乙酰半胱氨酸，D-葡萄糖钙，番茄红素，来自迷迭香提取物和白藜芦醇的ursolic酸。我们建议最初利用许多非常预测的体外和体内测试，以识别机制，并在标准条件下在各种浓度下在各种浓度下区分选定抑制剂的能力。然后，最有效的化合物将在使用7,12-二甲基苯甲酸[A]蒽（DMBA）引起的12-o-二甲基苯基苯基苯基酚-13-乙酸乙酸酯（TPA）（TPA）（TPA）的长期肿瘤实验中进行研究SKH-1小鼠中的多阶段癌变模型。最后，将在SENCAR小鼠以及SKH-1小鼠中的Sencar小鼠以及紫外线启动的TPA启动的TPA促进的TPA促进的皮肤癌模型中测试最佳的抗发射和抗肿瘤促进剂的组合。 The following Specific Aims will be studied: (i) identification, using various very predictive short-term in vitro and in vivo tests, including the DMBA-induced inflammatory-hyperplasia assay in SENCAR mice and the UV-induced erythema-hyperplasia assay in SKH-1 mice, the most promising mechanisms of anti-initiation and anti-tumor promotion as well as the most effective natural source抑制剂及其分娩是指局部与全身性（饮食）； （ii）分析使用DMBA发起的，TPA启动的，TPA启动的多阶段皮肤致癌模型的长期抗抗肿瘤和抗肿瘤促进促进有希望的自然源抑制剂在Sencar小鼠中的分析，以更好地了解其作用机制，并在以下组合研究中预测其作用和预测其性能； （iii）研究在SKH-1小鼠中，研究AIM 1和2中最佳的抗抑制剂和抗肿瘤启动子的长期抑制作用，在AIM 1和2中鉴定出对紫外线发射的TPA促进的TPA促进的多阶段皮肤癌的作用，以在化学诱导的和UV诱导的小鼠皮肤染色体的桥梁之间建立桥梁。 (iv) examining how various combinations of mechanistically different anti-initiators and antitumor promoting agents and also how various combinations of their delivery means, i.e., topical vs. systemic (dietary), inhibit DMBA-initiated, TPA-promoted skin carcinogenesis in SENCAR mice as well as UV-initiated, TPA-promoted skin carcinogenesis in SKH-1 mice, with the发现所选天然源抑制剂最明显的协同作用的观点。