Breast Cancer Chemoprevention Strategies

乳腺癌化学预防策略

• 批准号: 7392336
• 负责人: RAMESH C GUPTA
• 金额: $ 33.45万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7392336
• 关键词: 17p; Bexarotene; Binding; Biochemical; Biological Markers; Breast Cancer Model; Breast Cancer Prevention; Carcinogens; Catechol Estrogens; Catechols; Cell Proliferation; Cell-Free System; Chemoprevention; 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; Numbers; Oxidation-Reduction; PCNA gene; Pathway interactions; Performance; Plasma; Proliferation Marker; Property; Proteins; Proteome; Rattus; Relative (related person); Research Personnel; Risk; Risk Factors; Standards of Weights and Measures; Subgroup; System; Testing; Time; Tissues; Toxic effect; Week; Western Blotting; Woman; Work; adduct; base; carcinogenicity; concept; experience; foodborne; in vivo; indexing; lycopene; malignant breast neoplasm; 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）：流行病学研究已确定雌激素水平升高与乳腺癌的发生有关。特别是，天然激素17(3-雌二醇及其儿茶酚代谢物与乳腺癌的发展有关，并且人们认为雌激素儿茶酚会引起自由基介导的直接和/或间接DNA损伤，这可能导致基因突变我们通过新设计的 32P 后标记/TLC 系统在大鼠乳腺组织和人类乳腺组织中检测到了多种氧化和其他极性 DMA 加合物。与参考氧化加合物的色谱相似性表明组织 DNA 加合物源自自由基介导。这些结果表明加合物可能是由 17-3-雌二醇代谢物的氧化还原循环产生的。我们假设化学预防剂的组合将提供更有效的预防。这将通过以下方式实现：1) 使用不同作用方式的药物组合； 2）通过使用新型全身缓释装置来规避毒性。我们通过全身缓释系统和饮食提供的鞣花酸进行干预的初步结果在 ACI 大鼠模型中对 17-3-雌二醇介导的乳腺肿瘤发生产生了类似程度的抑制，支持了我们的工作假设。由经验丰富的研究人员组成的团队将进行以下具体研究来实现我们的目标：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) 确定候选药物减少 17-3-雌二醇诱导的体内细胞增殖的功效。 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，并将雌激素代谢的调节与肿瘤指数相关联。 4) 确定缓释装置递送的药物组合是否比单独药物更有效地抑制乳腺肿瘤发生。由此产生的数据将揭示，通过不同领域发挥作用的药物组合可以比单独的药物提供更全面的乳腺肿瘤预防，并且全身缓释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有效预防乳腺癌以及其他激素癌症的途径。