Breast Cancer Chemoprevention Strategies

乳腺癌化学预防策略

• 批准号: 7908147
• 负责人: RAMESH C GUPTA
• 金额: $ 9.93万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7908147
• 关键词: 17p; Bexarotene; Binding; Biochemical; Biological Markers; Breast Cancer Model; Breast Cancer Prevention; Carcinogens; Catechol Estrogens; Catechols; Cell Proliferation; Cell-Free System; Chemopreventive Agent; Clinical Research; Cytochromes; DNA Adducts; DNA Damage; DNA Repair; Data; Detox; Development; Devices; Diet; Disease; Dose; Ellagic Acid; Enzymes; Epidemiologic Studies; Estradiol; Estrogen Metabolism; Estrogen Receptors; Estrogen Replacement Therapy; Estrogens; Etiology; Exposure to; Female; Free Radicals; Future; Gene Mutation; Genes; Goals; Hormonal; Hormones; Human; Immunohistochemistry; Inbred ACI Rats; Incidence; Individual; Intervention; Lead; Lesion; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Tumorigenesis; Mammary gland; Measures; Mediating; Mediation; Metabolic; Methods; Modeling; Molecular Profiling; Oxidation-Reduction; Pathway interactions; Performance; Plasma; Proliferation Marker; Property; Proteins; Proteome; Rattus; Relative (related person); Research Personnel; Risk; Risk Factors; Subgroup; System; Testing; Time; Tissues; Toxic effect; Western Blotting; Woman; Work; adduct; base; cancer chemoprevention; carcinogenicity; experience; foodborne; high risk; in vivo; indexing; lycopene; malignant breast neoplasm; meetings; novel; oltipraz; prevent; tumor

DESCRIPTION (provided by applicant): Epidemiological studies have identified an association of elevated levels of estrogens with breast cancer development. In particular, the natural hormone, 17(3-estradiol and its catechol metabolites have been implicated in breast cancer development, and it is believed that estrogen catechols cause free radical mediated, direct and/or indirect DNA damage, which may lead to gene mutations and ultimately breast cancer. We have detected several oxidative and other polar DMA adducts in the mammary tissue of rats and in human breast tissues by newly devised 32P-postlabeling/TLC systems. Chromatographic similarity with reference oxidative adducts suggests that tissue DNA adducts originated from free radical-mediation. These results suggest that the adducts may have resulted from redox cycling of 17-3-estradiol metabolites. We hypothesize that combination of chemopreventive agents will provide more effective prevention of breast cancer than individual agents. This will be accomplished by 1) utilizing combination of agents with different modes of action; and 2) by using a novel systemic slow-release device to circumvent toxicity. Our preliminary results by interventions with ellagic acid delivered by systemic slow-release system and diet elicited similar degree of inhibition of 17-3-estradiol-mediated mammary tumorigenesis in the ACI rat model, supporting our working hypothesis. A team of experienced investigators will pursue the following specific studies to meet our goals: 1) Determine the efficacy of selected agents to modulate estrogen-metabolism and DNA repair in vivo. 2) Determine the efficacy of candidate agents to diminish 17-3-estradiol-induced cell proliferation in vivo. 3) Determine the efficacy of candidate agents to inhibit 17-3-estradiol-induced mammary tumorigenesis, and correlate modulation of estrogen metabolism with tumor indices. 4) Determine if combination of agents delivered by the slow-release device will provide more effective inhibition of mammary tumorigenesis compared with the individual agents. The resulting data will reveal that combination of agents working via different arenas can provide more complete prevention of mammary tumors than individual agents, and that the systemic slow-release delivery can circumvent toxicity by significantly reducing the effective dose. The data will also identify pathway(s) that can be targeted for effective prevention of breast cancer, and perhaps other hormonal cancers.

描述（由申请人提供）：流行病学研究已经确定了雌激素水平升高与乳腺癌发育的关联。特别是，天然激素，17个（3-雌二醇及其catechol代谢产物已与乳腺癌发育有关，人们认为雌激素catechols引起自由基介导的，直接和/或间接的DNA损害，这可能会导致基因突变，并最终导致乳腺癌，并最终在乳腺癌中发现了几种氧化和其他透明的DMA组织。 32P标签/TLC系统。利用与不同作用模式的代理组合； 2）使用一种新型的系统性缓释装置来规避毒性。我们的初步结果是通过全身性缓释系统提供的椭圆酸的干预措施，饮食在ACI大鼠模型中引起了类似的抑制17-3-雌二醇介导的乳腺肿瘤发生的程度，从而支持我们的工作假设。一组经验丰富的研究人员将进行以下特定研究以实现我们的目标：1）确定所选药物在体内调节雌激素代谢和DNA修复的功效。 2）确定候选药物在体内降低17-3-雌二醇诱导的细胞增殖的功效。 3）确定候选药物抑制17-3-雌二醇诱导的乳腺肿瘤发生的功效，并将雌激素代谢与肿瘤指数的调节相关。 4）确定与单个药物相比，缓释装置传递的药物的组合是否会更有效地抑制乳腺肿瘤。最终的数据将表明，通过不同领域工作的药物的组合可以比单个药物更完整地预防乳腺肿瘤，并且系统性缓慢释放的递送可以通过显着降低有效剂量来规避毒性。这些数据还将确定可以针对有效预防乳腺癌的途径，也许是其他激素癌。