Carcinogenic Metabolites formed from Antiestrogens

抗雌激素形成的致癌代谢物

• 批准号: 7175312
• 负责人: Judy L Bolton
• 金额: $ 21.59万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-08 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7175312
• 关键词: 4-Hydroxy-Tamoxifen; 4-hydroxytoremifene; Adverse effects; Aftercare; Agonist; Alkylation; Appendix; Binding; Biochemical; Biology; Breast; Breast Cancer Prevention; Breast Cancer Treatment; Cancer cell line; Carcinogenesis Mechanism; Carcinogens; Cell Line; Cell Nucleus; Cell Survival; Cells; Chemopreventive Agent; Chicago; Chronic; Classification; Clinic; Clinical Chemoprevention; Clinical Trials; Cytochrome P450; DNA; DNA Damage; Development; Doctor of Philosophy; Droloxifene; Endometrial Carcinoma; Endometrial Neoplasms; Endometrial adenocarcinoma; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptors; Estrogen receptor positive; Exposure to; Face; Free Radical Formation; Goals; Grant; High Risk Woman; Hormonal; Hormones; Human; Hydrolysis; Hydroxylation; Idoxifene; Illinois; In Vitro; Incidence; Individual; Inorganic Sulfates; Instruction; Invasive; Investigation; Lead; Liver; Measures; Mediating; Metabolism; Modeling; Monitor; Names; National Surgical Adjuvant Breast and Bowel Project; Numbers; Oxidation-Reduction; Pathway interactions; Personal Satisfaction; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacognosy; Placebos; Principal Investigator; Printing; Property; Protein Binding; Quinones; Raloxifene; Range; Rattus; Reaction; Reactive Oxygen Species; Recommendation; Relative (related person); Reporting; Research; Research Personnel; Research Project Grants; Risk; Role; Route; Safety; Selective Estrogen Receptor Modulators; Staging; Structure; Sulfhydryl Compounds; System; Tamoxifen; Testing; Toremifene; Toxic effect; Triphenylethylene; Tumor Promoters; Universities; Unspecified or Sulfate Ion Sulfates; Water; Woman; Wood material; Yang; adduct; base; behavior influence; benzoquinone; carcinogenesis; cellular targeting; chemical carcinogen; cofactor; cytotoxic; cytotoxicity; density; design; hormone therapy; in vivo; insight; interest; macromolecule; malignant breast neoplasm; programs; prophylactic; quinone methide; reaction rate; research study; size

Tamoxifen remains the endocrine therapy of choice in the treatment of all stages of hormone-dependent breast cancer. In addition, clinical trials are in progress to determine the potential of tamoxifen to act as a chemopreventive agent in women considered at high risk for developing breast cancer. However, several studies have raised concern over the safety of chronic treatment with this drug. Alternative SERMs may not be genotoxic because of different routes of metabolism which could lead to a decrease in amount and/or type of ultimate carcinogen(s). The central hypothesis of this project is that the formation of quinoids is an important mechanism qfCarcinogenesis andor cytotoxiciO, for certain antiestrogens. For example, tamoxifen can be metabolized to three inoids including two quinone methides and one o-quinone. The following specific aims are proposed: 1. Role of quinoids in the carcinogenic and cytotoxic effects of antiestrogens. We plan to examine the carcinogenic potential of quinoids formed from SERMs in cell lines. The biochemical effects of the antiestrogen quinoids will be investigated in human breast and endometrial cancer cell lines which are either estrogen receptor positive or negative. 2. Investigate the effect of quinoids structure on electrophilic and/or redox reactivity= The rates of reaction of the SERM quinoids with water and GSH will be measured. Reactions of selected intermediates with either estrogenic or antiestrogenic activity with deoxynucleosides and DNA will also be investigated and adduct structures elucidated. Redox active metabolites will be tested by monitoring changes in the concentrations of reduced cofactors, determining the formation of reactive oxygen species, and examining oxidative damage to DNA. 3. Determine if the antagonist/agonist activity of antiestrogen metabolites correlates with the extent of DNA damage in cell lines. We predict that excessive binding to the estrogen receptor which then translocates to the nucleus will be correlated with an increase in DNA damage. The Ishikawa cell system will be used to determine the estrogenic or antiestrogenic of the SERM metabolites. The results from the Ishikawa cell experiments will be compared to studies measuring binding of the antiestrogen metabolites to the estrogen receptors. Cellular DNA from estrogen receptor positive and negative cells lines will be isolated after treatment with the test compound. The DNA will be hydrolyzed to deoxynucleosides and examined for DNA damage. Finally, we will determine the extent of DNA damage induced in vivo by the most carcinogenic/cytotoxic antiestrogen metabolites using the rat liver model. These studies will elucidate the relative importance of alkylation and free radical formation for each antiestrogen, thereby enabling correlations of reactivity with structure from which general principles influencing the behavior of antiestrogen reactive metabolites in cells will emerge. PERFORMANCESITE(s)(organizationc, ity,state) Department of Medicinal Chemistry and Pharmacognosy University of Illinois at Chicago 833 S. Wood St. Chicago, IL 60612-7231 KEYPERSONNELS. eeinstructionosnPage11. Usecontinuationpagesasneededtoprovidetherequiredinformationintheformatshownbelow. Name Organization RoleonProject Judy L. Bolton, Ph.D. University of Illinois at Chicago P.I. John M. Pezzuto, Ph.D. University of Illinois at Chicago Co-Investigator Steven Swanson, Ph.D. University of Illinois at Chicago Co-Investigator Richard B. van Breemen, Ph.D. University of Illinois at Chicago Co-Investigator Emily Pisha, Ph.D. University of Illinois at Chicago Research Associate Linning Yu, B.S. University of Illinois at Chicago Research Assistant Fagen Zhang, Ph.D. University of Illinois at Chicago Research Associate Yanan Yang, B.S. University of Illinois at Chicago Research Assistant PHS398(Rev.4/98) Page2 g g Numberpagesconsecutivealyt thebottomthroughoutheapplication.Donotusesuffixesuchas 3a,3b. Principal Investigator/Program Director (Last, first, middle): Bolton, Judy L. The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. Type density and size must conform to limits and specifications provided in the PHS 398 Instructions. RESEARCH GRANT TABLE OF CONTENTS _Numbe_ Face Page ......................................................................................................................................................... 1 2- 2 Description,

他莫昔芬仍然是治疗激素依赖型乳房所有阶段的首选内分泌疗法 癌症。此外，临床试验正在进行中，以确定他莫昔芬作为一种 被认为是乳腺癌高危人群的化学预防药物。然而，有几项研究 已经引起了人们对这种药物慢性治疗的安全性的担忧。替代的SERM可能不会有遗传毒性 因为不同的新陈代谢途径可能导致终极代谢的数量和/或类型的减少 致癌物(S)。这个项目的中心假设是藜麦的形成是一种重要的机制 对某些抗雌激素有致癌和或细胞毒性作用。例如，他莫昔芬可以代谢成三种 类儿茶素类化合物，包括两个甲基苯二酚和一个邻苯二酚。提出了以下具体目标：1.角色 藜芦醇在抗雌激素的致癌和细胞毒作用中的作用。我们计划检查致癌物质 SERM形成的藜麦类化合物在细胞系中的潜力。抗雌激素藜麦的生物化学效应 在雌激素受体阳性或阳性的人乳腺和子宫内膜癌细胞系中进行研究 不是。2.研究藜麦碱类化合物的结构对亲电和/或氧化还原反应性的影响 将测量SERM藜麦与水和GSH的反应。选定的中间体与 脱氧核苷和DNA的雌激素或抗雌激素活性也将被研究和加成。 结构已阐明。氧化还原活性代谢物将通过监测浓度的变化进行测试 减少辅因子，确定活性氧物种的形成，并检查对DNA的氧化损伤。 3.确定抗雌激素代谢物的拮抗剂/激动剂活性是否与DNA的程度相关 对细胞系的破坏。我们预测，过度与雌激素受体结合，然后转移到 细胞核将与DNA损伤的增加相关。石川电池系统将被用来确定 SERM代谢物的雌激素样或抗雌激素样。石川电池实验的结果将是 与测量抗雌激素代谢物与雌激素受体结合的研究相比。细胞DNA 从雌激素受体阳性和阴性的细胞系中分离出经试验化合物处理后的细胞系。这个 DNA将被水解成脱氧核苷，并检查DNA损伤。最后，我们将确定 大多数致癌/细胞毒性抗雌激素代谢物对大鼠体内DNA损伤的程度 肝脏模型。这些研究将阐明烷基化和自由基形成对每一个过程的相对重要性。 抗雌激素，从而使反应性与结构的相关性，从这些结构的一般原则影响 细胞中会出现抗雌激素活性代谢物的行为。 工作人员(S)(组织、身份、状态) 药用化学与生药学系 伊利诺伊大学芝加哥分校 833 S.伍德街 伊利诺伊州芝加哥 60612-7231 KEYPERSONELS英语教学11页。Usecontinuationpagesasneededtoprovidetherequiredinformationintheformatshownbelow. 名称组织角色项目 朱迪·L·博尔顿，伊利诺伊大学芝加哥分校博士。 约翰·M·佩祖托，伊利诺伊大学芝加哥分校博士，共同研究员 史蒂文·斯旺森博士，伊利诺伊大学芝加哥分校共同研究员 理查德·范·布里门，伊利诺伊大学芝加哥分校博士，共同研究员 艾米丽·皮莎，伊利诺伊大学芝加哥研究分校博士 联想 余琳宁，伊利诺伊大学芝加哥分校理学士 助理员 张法根，博士，伊利诺伊大学芝加哥分校研究 联想 杨亚南，伊利诺伊大学芝加哥分校理学士 助理员 PHS398(版本4/98)页2 g g 连续分析thebottomthroughoutheapplication.Donotusesuffixesuchas 3a、3b的页数。 首席研究员/项目主任(最后、第一、中间)：Bolton，Judy L. 必须在每张打印页和每张续页的顶部提供首席调查员/项目主任的姓名。 字体密度和大小必须符合PHS 398说明书中提供的限制和规格。 研究补助金 目录 _数字_ 主页...........................................................................................................................................1 2-2 描述，