PREVENTION OF MAMMARY CARCINOGENESIS BY QUERCETIN

本申请的总体目标是进一步研究 槲皮素作为化学预防剂的功效，并研究其 作用机制。 在动物研究中，槲皮素显著抑制了 二甲基苯并（α）蒽（DMBA）-和N-的多重性 亚硝基甲脲诱导的大鼠乳腺癌和结肠癌 小鼠 此外，包括槲皮素在内的某些黄酮类化合物抑制肿瘤 12-O-十四酰基-佛波醇-13-乙酸酯在两个阶段中的促进作用 小鼠表皮的致癌作用。 槲皮素还抑制DHBA诱导的 小鼠乳腺器官培养系统中的乳腺病变， 在我们的实验室里。 在抑制的机制参与 槲皮素的致癌作用尚不清楚。 四种基本酶参与 在信号转导通路中的作用被抑制， 槲皮素：蛋白激酶C，蛋白酪氨酸激酶，脂氧合酶，和 拓扑异构酶Ⅱ监测这些酶的活性， 它们在大鼠乳腺癌发生过程中的底物， 化学预防将提供更好的理解在体内模式， 该化合物的作用。 这些机制研究也可能导致 鉴定可增强槲皮素功效的其它药剂 在预防乳腺肿瘤方面。 我们建议： 1.进一步阐明槲皮素在DMBA中的化学预防作用， 诱导的乳腺癌模型， 2.检查槲皮素是否抑制起始和/或促进 癌症发生的阶段， 3.确定其影响是否对发展有选择性 肿瘤依赖性或非依赖性肿瘤，和 4.评估槲皮素的酶改变作用在 致癌作用

The overall objectives of this application are to study further quercetin's efficacy as a chemopreventive agent, and to investigate its mechanism of action. In animal studies, quercetin significantly inhibited the incidence and multiplicity of dimethylbenz(alpha)anthracene(DMBA)- and N- nitrosomethylurea-induced mammary cancers in rats and colon tumors in mice. Additionally, certain flavonoids including quercetin inhibit tumor promotion by l2-O-tetradecanoyl-phorbol-l3-acetate in the two stage carcinogenesis in mouse epidermis. Quercetin also inhibits DHBA-induced mammary lesions in a mouse mammary gland organ culture system, developed in our laboratory. The mechanism involved in the inhibition of carcinogenesis by quercetin is unclear. Four fundamental enzymes involved in the signal transduction pathway have been reported to be inhibited by quercetin: protein kinase C, protein tyrosine kinase, lipoxygenase, and topoisomerase II. Monitoring the activities of some of these enzymes and their substrates in rat mammary glands during carcinogenesis and chemoprevention will provide a better understanding of the in vivo mode of action of this compound. These mechanistic studies may also lead to the identification of other agents that may enhance the efficacy of quercetin in preventing mammary tumors. We propose to: 1. clarify further the chemopreventive action of quercetin in a DMBA- induced mammary cancer model, 2. examine whether quercetin inhibits the initiation and/or promotion phases of carcinogenesis, 3. determine whether its effect is selective against the development of hormone-dependent or -independent tumors, and 4. evaluate the role of quercetin's enzyme-altering effects in carcinogenesis.