Hormonal Induction Mouse Models of Prostate Cancer

前列腺癌激素诱导小鼠模型

• 批准号: 7895865
• 负责人: MAARTEN C BOSLAND
• 金额: $ 7.85万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895865
• 关键词: Address; Androgens; Animal Model; Animals; Antioxidants; Applications Grants; Back; Breeding; Cell Proliferation; Chemoprevention; Chemopreventive Agent; Chronic; Clinical; Dependence; Development; Disease Progression; Dose; Endocrine; Epigallocatechin Gallate; Estradiol; Estrogens; Etiology; Evaluation; Exposure to; Feasibility Studies; Fibrous capsule of kidney; Frequencies; Funding; Future; Gene Knock-Out Model; Gene Proteins; Genes; Gland; Goals; Grant; Hand; Hormonal; Hormones; Human; Implant; Incidence; Injection of therapeutic agent; Knock-out; Laboratories; Large T Antigen; Lead; Learning; Lesion; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Methylnitrosourea; Modeling; Mouse Strains; Mus; NIH Program Announcements; NKX3-1 gene; Nude Mice; Outcome; Oxidative Stress; PTEN gene; Play; Pre-Clinical Model; Prevention Research; Principal Investigator; Process; Prostate; Prostate Cancer Progress Review Group; Prostate carcinoma; Prostatic; Prostatic Intraepithelial Neoplasias; Prostatic Neoplasms; Rattus; Recombinants; Reporting; Research; Role; Selenium; Sequential Treatment; Silastic; Simian virus 40; Staging; Testing; Testosterone; Time; Tissues; Transgenic Mice; Translating; Tumor Promoters; Uncertainty; Vitamin E; Work; alitretinoin; anticancer research; cancer chemoprevention; cancer prevention; carcinogenesis; cost; dehydroepiandrosterone; efficacy testing; innovation; interest; lycopene; mouse model; neoplastic; novel; pre-clinical; probasin; programs; promoter; prostate carcinogenesis; research study; response; sex; soy protein isolate; steroid hormone; subcutaneous; tumor

DESCRIPTION (provided by applicant): This proposal is in response to PA-08-055, "Cancer Prevention Research Small Grant Program (R03)", proposing pilot-feasibility studies that address the development of innovative animal models to mimic the human [prostate] cancer process in order to expedite research in cancer prevention. Animal models of prostate carcinogenesis are essential in the development of chemopreventive agents. Only two models have been used to screen agents in a systematic fashion, the MNU (methylnitrosourea) plus testosterone rat model and the C3(1)-probasin-SV40-large T antigen transgenic mouse model, but neither model is ideal. There is clearly a need for additional models, particularly mouse models that recapitulate the various stages of human prostate cancer development and involve androgen action as human prostate carcinogenesis does. Mouse models have several major advantages over rat models, including their lower cost, the much smaller amounts of chemoprevention agents they require, and the potential to have shorter latent periods than those in rat models that typically require 12-13 months of treatment. These three issues have seriously impaired chemoprevention efficacy testing in animal models of prostate cancer. We propose here to test the hypothesis that two different experimental strategies for induction of prostate cancer that have been demonstrated to work in rats can be successfully applied to mice. These strategies include one model that has been used most extensively in preclinical chemoprevention efficacy testing, namely the MNU (methylnitrosourea) plus testosterone rat model. The other rat model, which entirely depends on steroid hormone action and involves oxidative stress mechanisms, is the so-called NBL (or Noble) rat model involving combined exposure to estradiol and testosterone. We propose to translate the steroid hormone prostate cancer induction approaches of the NBL and MNU plus testosterone rat models to mice. If successfully yielding a hormonally-induced prostate carcinogenesis mouse model, this will pave the way for R01-type and other grant applications applying this model (1) to identify efficacious prostate cancer chemoprevention agents and (2) to tests specific mechanistic hypotheses genetically modified mice treated with steroid hormones. The specific aims of the project are to determine whether prostate carcinomas and/or lesions comparable to human prostatic intraepithelial neoplasia (PIN) can be induced in mice by (1) MNU plus testosterone and (2) estradiol plus testosterone. The mouse models arising from this project may be well suited for the evaluation of chemopreventive activity of new candidate agents including antioxidants. Both approaches may also lead to development of new mouse models of prostate carcinogenesis for mechanistic research.

描述(由申请人提供)： 这项建议是对PA-08-055“癌症预防研究小额资助计划(R03)”的响应，该计划提出了试验性可行性研究，旨在开发模拟人类[前列腺癌]癌症过程的创新动物模型，以加快癌症预防研究。前列腺癌的动物模型在化学预防药物的开发中是必不可少的。只有两种模型被用于系统地筛选药物，即MNU(甲基亚硝胺)+睾酮大鼠模型和C3(1)-PROPOWER-SV40-大T抗原转基因小鼠模型，但这两种模型都不是理想的。显然需要更多的模型，特别是小鼠模型，这些模型概括了人类前列腺癌发展的不同阶段，并涉及雄激素的作用，就像人类前列腺癌的发生一样。与大鼠模型相比，小鼠模型有几个主要优势，包括它们的成本更低，所需的化学预防药量要少得多，而且与通常需要12-13个月治疗的大鼠模型相比，潜伏期可能更短。这三个问题严重影响了前列腺癌动物模型的化学预防效果测试。我们在这里提出的假设是，两种不同的诱导前列腺癌的实验策略已经被证明在大鼠身上有效，可以成功地应用于小鼠。这些策略包括一种在临床前化学预防有效性测试中使用最广泛的模型，即MNU(甲基亚硝脲)+睾酮大鼠模型。另一种完全依赖类固醇激素作用并涉及氧化应激机制的大鼠模型，即所谓的NBL(或Noble)大鼠模型，涉及雌二醇和睾酮的联合暴露。我们建议将NBL和MNU+睾酮大鼠模型的类固醇激素前列腺癌诱导方法移植到小鼠身上。如果成功地产生了激素诱导的前列腺癌小鼠模型，这将为应用该模型的R01型和其他赠款应用铺平道路：(1)确定有效的前列腺癌化学预防药物；(2)测试使用类固醇激素治疗的特定机制假说的转基因小鼠。该项目的具体目标是确定(1)MNU+睾酮和(2)雌二醇+睾酮能否诱发前列腺癌和/或类似于人类前列腺上皮内瘤变(PIN)的病变。该项目建立的小鼠模型可能非常适合于评估包括抗氧化剂在内的新候选制剂的化学预防活性。这两种方法也可能导致新的前列腺癌小鼠模型的发展，用于机理研究。