MCF10DCIS.com as a preclinical chemopreventive screen

MCF10DCIS.com 作为临床前化学预防筛查

• 批准号: 6620013
• 负责人: FRED Raymond MILLER
• 金额: $ 7.45万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620013
• 关键词: SCID mouse; antineoplastics; biomarker; breast neoplasms; cancer prevention; chemoprevention; diet therapy; drug screening /evaluation; estradiol; fenretinide; flavones; hormone related neoplasm /cancer; indoles; interferon alpha; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; tamoxifen

Our objective is to validate a preclinical xenograft model for assessment of the ability of chemical agents to alter surrogate end- point biomarker (SEB) expression in breast carcinoma in situ. We have developed a human breast epithelial cell line, MCF10DCIS.com, which produces ductal carcinoma in situ of the comedo type. Nearly one gram of tissue is obtained 6-8 weeks after injecting 1x10/7 cells in Matrigel into immune deficient mice. We will be able to validate results with the model by direct comparison with results of a clinical study being conducted at the Karmanos Cancer Institute in which patients diagnosed with DCIS are given 100 mg of soy isoflavones daily for three weeks prior to surgery. Surgical specimens are analyzed for expression of a number of markers including connexin 43, p21, bax, bcl-2, p21, and CDK5. However, the preclinical model allows us to treat groups of xenografted mice with chemopreventive agents and determine expression of biomarkers in lesions from treated and untreated at multiple intervals rather than the single time point possible in the clinical study. We will also be able to test additional chemopreventive agents, doses, and combinations. The size of the xenograft lesions will allow us to look at chemopreventive agents, doses, and combinations. The size of the xenograft lesions will allow us to look at many additional biomarkers, both before and after treatment, than the sparse material likely to be available from the clinical specimens. Once validated, MCF10DCIS.com will provide a unique xenograft model of human ductal carcinoma in situ for rapid screening of putative chemopreventive agents. In combination with the MCF10AT1 in situ for rapid screening of putative chemopreventive agents. In combination with the MCF10AT1 xenograft model of progressive premalignant breast disease, the model will also provide a means of validating the relevance of different SEBs for screening chemopreventive agents.

我们的目的是验证临床前异种移植模型，以评估化学制剂改变乳腺癌原位替代终点生物标志物（SEB）表达的能力。我们已经开发了一种人类乳腺上皮细胞系MCF10DCIS.com，它可以产生粉刺型导管原位癌。免疫缺陷小鼠注射1x10/7细胞后6-8周可获得近1克组织。我们将能够通过与Karmanos癌症研究所进行的一项临床研究的结果直接比较来验证该模型的结果，在该研究中，诊断为DCIS的患者在手术前三周内每天给予100毫克大豆异黄酮。分析手术标本中一些标记物的表达，包括连接蛋白43、p21、bax、bcl-2、p21和CDK5。然而，临床前模型允许我们用化学预防药物治疗异种移植小鼠组，并在多个间隔时间（而不是临床研究中可能的单一时间点）测定治疗和未治疗的病变中生物标志物的表达。我们还将能够测试其他化学预防剂、剂量和组合。异种移植物病变的大小将使我们能够考虑化学预防剂、剂量和组合。异种移植物病变的大小将使我们能够在治疗前后看到许多额外的生物标志物，而不是从临床标本中可能获得的稀疏材料。一旦验证，MCF10DCIS.com将提供一个独特的人类导管原位癌异种移植模型，用于快速筛选推定的化学预防药物。结合MCF10AT1原位快速筛选推定的化学预防剂。结合MCF10AT1进行性癌前乳腺疾病的异种移植模型，该模型还将为验证不同seb在筛选化学预防药物方面的相关性提供一种手段。