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雌激素水平升高与乳腺癌发展有关。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，人们认为雌激素儿茶酚引起自由基介导的，直接和/或间接的DNA损伤，这可能导致基因突变并最终导致乳腺癌。我们通过新设计的32p标签后/TLC系统在大鼠和人乳腺组织中检测到几种氧化和其他极性DMA加合物。与参考氧化加合物的色谱相似性表明组织DNA加合物起源于自由基介导。这些结果表明，这些加合物可能是由17-3-雌二醇代谢产物的氧化还原循环引起的。我们假设联合使用化学预防药物将比单独使用药物更有效地预防乳腺癌。这将通过1)利用具有不同作用模式的药物组合来实现；2)利用一种新型的全身缓释装置来规避毒性。在ACI大鼠模型中，通过全身缓释系统和饮食给药鞣花酸对17-3-雌二醇介导的乳腺肿瘤发生的抑制程度相似，我们的初步结果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具体研究，以实现我们的目标：1)确定选定药物在体内调节雌激素代谢和DNA修复的功效。2)确定候选药物对17-3-雌二醇诱导的细胞增殖的体内抑制作用。3)确定候选药物对17-3-雌二醇诱导的乳腺肿瘤发生的抑制作用，并将雌激素代谢调节与肿瘤指标的关系联系起来。4)确定由缓释装置递送的药物联合使用是否比单独使用药物更有效地抑制乳腺肿瘤的发生。由此得出的数据将揭示，通过不同途径联合使用药物比单独使用药物更能完全预防乳腺肿瘤，并且全身缓释给药可以通过显著降低有效剂量来规避毒性。这些数据还将确定有效预防乳腺癌和其他激素类癌症的途径。