Carcinogenic Metabolites formed from Antiestrogens

抗雌激素形成的致癌代谢物

基本信息

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
项目类别：
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

项目摘要

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,

他莫昔芬在治疗激素依赖性乳房的所有阶段中仍然是内分泌疗法癌症。此外，临床试验正在进行中，以确定他莫昔芬的潜力被认为患乳腺癌的高风险的女性化学预防剂。但是，有几项研究对这种药物的慢性治疗的安全提出了担忧。替代性Serm可能不是遗传毒性由于新陈代谢的不同途径，可能导致数量减少和/或最终类型致癌物。该项目的核心假设是形成二氨酸是一个重要的机制 qfcarcinogenesegosty andor细胞毒素，用于某些抗雌激素。例如，他莫昔芬可以代谢为三个包括两种醌甲基和一个O-夸酮的固醇。提出了以下特定目标：1。抗雌激素的致癌和细胞毒性作用中的喹啉的。我们计划检查致癌由细胞系中的Serm形成的二氨基型的潜力。抗雌激素的二甲体的生化作用将可以在人乳房和子宫内膜癌细胞系中进行研究，雌激素受体阳性或消极的。 2。研究喹啉结构对亲电和/或氧化还原反应性的影响= 将测量serm喹啉与水和GSH的反应。选定中间体的反应脱氧核苷和DNA的雌激素或抗雌激素活性也将被研究并加入结构阐明了。氧化还原活性代谢物将通过监视浓度的变化来测试减少辅因子，确定活性氧的形成，并检查对DNA的氧化损伤。 3。确定抗雌激素代谢产物的拮抗剂/激动剂活性是否与DNA的程度相关细胞线的损坏。我们预测，与雌激素受体的结合过度结合，然后易位细胞核将与DNA损伤的增加相关。 Ishikawa细胞系统将用于确定 Serm代谢产物的雌激素或抗雌激素。 Ishikawa细胞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 用测试化合物处理后，将分离出雌激素受体阳性和阴性细胞系。这 DNA将被水解为脱氧核苷，并检查是否有DNA损伤。最后，我们将确定使用大鼠使用大多数致癌/细胞毒性抗疾病代谢物在体内诱导的DNA损伤程度肝模型。这些研究将阐明每种烷基化和自由基形成的相对重要性抗雌激素，从而实现了反应性与结构的相关性抗雌激素反应性代谢物在细胞中的行为将出现。表演现场（S）（组织，ITY，State）药物和药学系伊利诺伊大学芝加哥 833 S. Wood St. 伊利诺伊州芝加哥 60612-7231 Keypersonnels。 EEINSTRUCTIONOSNPAGE11。 usecontinuationPagesAsneedToprovidEtherequiredInformination in theFormatShownbelow。名称组织角色注射器 Judy L. Bolton博士伊利诺伊大学芝加哥P.I. John M. Pezzuto博士伊利诺伊大学芝加哥共同投资者史蒂文·斯旺森（Steven Swanson）博士伊利诺伊大学芝加哥共同投资者理查德·范·布雷伦（Richard B. Van Breemen）博士伊利诺伊大学芝加哥共同投资者艾米丽·皮沙（Emily Pisha）博士伊利诺伊大学芝加哥研究联系 B.S. Linning Yu伊利诺伊大学芝加哥研究助手 Fagen Zhang博士伊利诺伊大学芝加哥研究联系 Yanan Yang，学士伊利诺伊大学芝加哥研究助手 PHS398（Rev.4/98）Page2 G G G G numberPagesConsecutiveAlyt thebottomthroughoutheapplication.donotuseusefixesuchas 3a，3b。首席研究员/计划主任（最后，第一，中间）：博尔顿，朱迪·L。必须在每个印刷页面的顶部和每个延续页面的顶部提供主要调查员/计划主管的名称。类型密度和大小必须符合PHS 398说明中提供的限制和规格。研究赠款目录 _numbe_ 面页................................................................................................................ ................................................................................. ................................................................................. ..... 1 2-2 描述，