A Preclinical Chemopreventive Model in Prostate Cancer

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缓前列腺癌(CAP)进展的药物。虽然初步结果耐人寻味，但缺乏支持其有效性的机械证据和确定最佳治疗方案的剂量学数据。此外，许多研究正在动物身上进行，以开发生物标记物和筛选潜在的化疗药物，但对其对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药物进行分类，我们将能够开发出最大限度地减少前列腺癌生长的治疗方案。该应用的目的是通过前列腺癌致癌物PhIP(2-amino-1-methyl-6-phenylimidazo[4，5-b]pyridine)结合睾酮治疗诱导大鼠CAP来建立这样的模型。PhIP被选为模型化合物是因为它与人类有关：它存在于人类饮食中，在人体组织中被检测到，并可能有助于解释非裔美国人相对于高加索人更高的CAP发生率。 具体地说，我们将：(1)确定在PhIP诱导的肿瘤形成过程中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；以及(2)评估选定的化学预防药物是否降低DNA加合物水平，减少肿瘤形成和/或改变肿瘤生长。 一旦开发出来，这个模型将被用于研究哪些假定的化学保护剂确实能减少前列腺癌的发生，并在投资于人体研究之前确定最有效的治疗方案，包括评估单一药剂和联合疗法。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，并最终将为研究化学预防药物的药理学和毒理学提供一种手段。该模型也将有助于从病因和化学预防的角度研究饮食在前列腺癌中的重要性。通过将研究投资集中在那些实际上已经证明有能力影响前列腺癌发生的领域，使用这种模式应该会导致更快地制定有效的治疗选择或改变生活方式的建议。

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.