A Preclinical Chemopreventive Model in Prostate Cancer

前列腺癌的临床前化学预防模型

基本信息

项目摘要

DESCRIPTION (provided by applicant) A number of clinical studies are underway to test agents that may prevent or delay the progression of prostate cancer (CaP). While preliminary results are intriguing, mechanistic evidence supporting their effectiveness and dosimetric data identifying optimum treatment regimens is lacking. In addition, many studies are being performed in animals to develop biomarkers and screen potential chemotherapeutic agents, with little understanding of their validity for CaP. We therefore believe that there is a critical need for a standardized model to investigate the effectiveness, safety and molecular mechanisms involved in CaP chemoprevention. It is our hypothesis that by using a CaP model to classify chemopreventive agents according to mechanism of action, we will be able to develop therapeutic regimens that maximize the potential for reducing prostate tumor growth. The purpose of this application is to develop such a model with rats by inducing CaP with the prostate carcinogen PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) in combination with testosterone treatment. PhIP has been chosen as the model compound because it has human relevance: it is present in the human diet, has been detected in human tissues, and may help explain the higher CaP incidence in African Americans relative to Caucasians. Specifically we will: (1) Determine the histopathological changes occurring in the rat prostate during PhIP-induced tumorigenesis and determine whether intermediate changes can be defined at the histological and molecular level; and (2) Assess whether selected chemopreventive agents reduce DNA adduct levels and reduce tumor formation and/or change tumor growth. Once developed, this model will be used to study, which putative chemoprotective agents actually do cause a reduction in prostate cancer and determine the most effective treatment schedule including assessment of single agent and combination therapy, prior to investing in human studies. In addition, the model will be useful for identifying interactions between drugs, diet and chemoprevention treatments, and will ultimately provide a means to study the pharmacology and toxicology of chemopreventive agents. This model will also be useful for studying the importance of diet in prostate cancer, both from a causation and chemoprevention standpoint. Use of such a model should lead to faster development of effective treatment options or lifestyle change recommendations by virtue of focusing research investment on those areas, which have actually demonstrated the ability to affect prostate carcinogenesis.
描述(由申请人提供)许多临床研究正在进行中,以测试可能预防或延迟前列腺癌(CaP)进展的药物。虽然初步结果很有趣,但缺乏支持其有效性的机制证据和确定最佳治疗方案的剂量测定数据。此外,许多研究正在动物中进行,以开发生物标志物和筛选潜在的化疗药物,但对它们对CaP的有效性知之甚少。因此,我们认为,迫切需要一个标准化的模型来研究CaP化学预防的有效性,安全性和分子机制。我们的假设是,通过使用CaP模型根据作用机制对化学预防剂进行分类,我们将能够开发出最大限度地降低前列腺肿瘤生长潜力的治疗方案。本申请的目的是通过用前列腺致癌物PhIP(2-氨基-1-甲基-6-苯基咪唑并[4,5-B]吡啶)与睾酮治疗组合诱导CaP来用大鼠开发这种模型。选择PhIP作为模型化合物是因为它具有人类相关性:它存在于人类饮食中,已在人体组织中检测到,并且可能有助于解释非洲裔美国人相对于高加索人的较高CaP发病率。 具体而言,我们将:(1)确定在PhIP诱导的肿瘤发生期间大鼠前列腺中发生的组织病理学变化,并确定是否可以在组织学和分子水平上定义中间变化;和(2)评估所选的化学预防剂是否降低DNA加合物水平并减少肿瘤形成和/或改变肿瘤生长。 一旦开发出来,该模型将用于研究,哪些假定的化学保护剂实际上确实会导致前列腺癌的减少,并确定最有效的治疗方案,包括评估单一药物和联合治疗,然后再投资于人体研究。此外,该模型将有助于确定药物,饮食和化学预防治疗之间的相互作用,并最终提供一种手段来研究化学预防剂的药理学和毒理学。该模型也将有助于研究饮食在前列腺癌中的重要性,无论是从因果关系还是从化学预防的角度来看。使用这样的模型应该导致更快地开发有效的治疗方案或生活方式改变的建议,通过集中研究投资于这些领域,这实际上已经证明了影响前列腺癌的能力。

项目成果

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Kenneth W. Turteltaub其他文献

Benzo[a]pyrene (BaP) metabolites predominant in human plasma following escalating oral micro-dosing with [sup14/supC]-BaP
在口服递增微剂量[sup14/supC]-苯并[a]芘后,人血浆中占主导地位的苯并[a]芘(BaP)代谢物
  • DOI:
    10.1016/j.envint.2021.107045
  • 发表时间:
    2022-01-15
  • 期刊:
  • 影响因子:
    9.700
  • 作者:
    Monica L. Vermillion Maier;Lisbeth K. Siddens;Jamie M. Pennington;Sandra L. Uesugi;Kim A. Anderson;Lane G. Tidwell;Susan C. Tilton;Ted J. Ognibene;Kenneth W. Turteltaub;Jordan N. Smith;David E. Williams
  • 通讯作者:
    David E. Williams

Kenneth W. Turteltaub的其他文献

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{{ truncateString('Kenneth W. Turteltaub', 18)}}的其他基金

Development of laser spectroscopic methods for quantification of 14C
14C 定量激光光谱方法的开发
  • 批准号:
    8743804
  • 财政年份:
    2014
  • 资助金额:
    $ 7.43万
  • 项目类别:
Development of laser spectroscopic methods for quantification of 14C
14C 定量激光光谱方法的开发
  • 批准号:
    8931002
  • 财政年份:
    2014
  • 资助金额:
    $ 7.43万
  • 项目类别:
CANCER CHEMOPREVENTIVE AGENTS ON DNA ADDUCT BY DIETARY PROSTATE CARCINOGEN PHIP
针对膳食前列腺癌 PHIP DNA 加合物的癌症化学预防剂
  • 批准号:
    7602405
  • 财政年份:
    2007
  • 资助金额:
    $ 7.43万
  • 项目类别:
CANCER CHEMOPREVENTIVE AGENTS ON DNA ADDUCT BY DIETARY PROSTATE CARCINOGEN PHIP
针对膳食前列腺癌 PHIP DNA 加合物的癌症化学预防剂
  • 批准号:
    7358997
  • 财政年份:
    2006
  • 资助金额:
    $ 7.43万
  • 项目类别:
Core--DEVELOPMENT OF BIOLOGICAL SAMPLE METHODS
核心--生物样品方法开发
  • 批准号:
    6975546
  • 财政年份:
    2004
  • 资助金额:
    $ 7.43万
  • 项目类别:
A Preclinical Chemopreventive Model in Prostate Cancer
前列腺癌的临床前化学预防模型
  • 批准号:
    6692663
  • 财政年份:
    2003
  • 资助金额:
    $ 7.43万
  • 项目类别:
BENZENE ADDUCTED PROTEINS IN MOUSE BONE MARROW & LIVER ACCELERATOR
小鼠骨髓中的苯内加蛋白
  • 批准号:
    6660165
  • 财政年份:
    2002
  • 资助金额:
    $ 7.43万
  • 项目类别:
DEVELOPMENT OF BIOLOGICAL SAMPLE METHODS
生物样品方法的开发
  • 批准号:
    6660159
  • 财政年份:
    2002
  • 资助金额:
    $ 7.43万
  • 项目类别:
BENZENE ADDUCTED PROTEINS IN MOUSE BONE MARROW & LIVER ACCELERATOR
小鼠骨髓中的苯内加蛋白
  • 批准号:
    6504575
  • 财政年份:
    2001
  • 资助金额:
    $ 7.43万
  • 项目类别:
DEVELOPMENT OF BIOLOGICAL SAMPLE METHODS
生物样品方法的开发
  • 批准号:
    6504569
  • 财政年份:
    2001
  • 资助金额:
    $ 7.43万
  • 项目类别:

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