Methyl-selenium for prostate cancer chemoprevention

描述(由申请人提供)：正在进行的硒-维生素E癌症试验(SELECT)正在测试单独或与维生素E结合形式的硒(Se)在大约32,400名北美男性中预防前列腺癌(PCA)的有效性。结果预计将在十年内公布。如果积极的预防效果得到证实，使用这种形式的硒对公众健康的影响是不言而喻的，这将为进一步的临床试验提供突出的动力，以寻找更有效的硒制剂，实现更大的预防效益。如果答案是否定的，那么寻找有效的硒制剂就显得尤为紧迫。我们和其他人的细胞培养研究表明，甲基硒醇及其直接前体如甲基硒酸(MSEA，我们统称为甲基硒)在抑制血管生成开关机制、诱导G1期细胞周期停滞、减少AKT激活和诱导caspase介导的细胞凋亡等一系列抗前列腺癌过程中比Semet有效得多。我们和其他人最近表明，甲基硒抑制雄激素受体(AR)的表达和信号转导，这对前列腺癌的发展至关重要。此外，我们现在已经在初步研究中发现，每天口服MSEA和甲基硒半胱氨酸(MSEC)对裸鼠体内的DU145人PCA异种移植瘤的生长具有剂量依赖性的抑制作用，而相同剂量的SeMet则没有。我们假设，甲基硒通过抑制肿瘤血管生成、细胞周期停滞和/或诱导caspase介导的细胞凋亡以及前列腺器官特异性抑制AR表达和信号转导，在体内通过广谱抗癌作用来预防前列腺癌。为了验证这一假设，我们在雄激素依赖(AD)和雄激素非依赖(AI)的PCa异种移植模型和TRAMP(转基因前列腺癌小鼠前列腺癌)原发前列腺癌模型中提出了3个特异性靶点。我们将建立MSEA和MSSEC与SEMET在体内的化学预防效果，并表征和验证关键的机制生物标记物，如抑制血管生成的血管内皮生长因子和抑制AR和PSA抑制雄激素信号。我们期望提供有价值的疗效和生物标记物数据，以指导未来具有更大前列腺特异性靶向作用的甲基硒临床翻译研究的设计。他们还将对预测和解释选定研究的结果具有洞察力。 叙述：这些研究的结果将提供有价值的体内疗效和生物标志物数据，以指导未来甲基硒用于前列腺癌化学预防的人类临床试验的设计。它们还将对预测和解释正在进行的硒癌症预防试验的结果具有指导意义。

DESCRIPTION (provided by applicant): The ongoing Selenium-vitamin E Cancer Trial (SELECT) is testing the efficacy of selenium (Se) in the form of selenomethionine (SeMet) alone or in combination with vitamin E to prevent prostate cancer (PCa) in a cohort of some 32,400 North American men. The results are expected in a decade. If a positive preventive efficacy is confirmed, the public health impact of using this form of Se is self-evident, and this will provide an outstanding impetus for further clinical trials to identify more efficacious Se agents to realize even greater preventive benefits. If negative, the quest for effective Se agents takes on significant urgency. Cell culture studies by us and others suggest that methylselenol and its immediate precursors such as methylseleninic acid (MSeA, we refer them collectively as methyl-Se) are much more efficacious than SeMet with respect to a number of anti-PCa processes such as inhibiting angiogenic switch mechanisms, inducing G1 cell cycle arrest, decreasing AKT activation and inducing caspase-mediated apoptosis. We and others have recently shown that methyl-Se inhibits androgen receptor (AR) expression and signaling, which are crucial for PCa development. Furthermore, we have now in pilot studies found that MSeA and methylselenocysteine (MSeC) given by daily oral dosing exerted dose-dependent inhibition of DU145 human PCa xenograft growth in athymic nude mice and SeMet at the same dosage did not. We hypothesize that methyl-Se prevents PCa in vivo by its broad-spectra anti-cancer actions through inhibiting tumor angiogenesis, cell cycle arrest and/or an induction of caspase-mediated apoptosis as well as by the prostate organ-specific inhibition of AR expression and signaling. To test this hypothesis, we propose 3 specific aims in both androgen-dependent (AD) and androgen-independent (AI) PCa xenograft models and the TRAMP (TRansgenic Adenocarcinoma Mouse Prostate) primary prostate carcinogenesis model. We will establish the in vivo chemopreventive efficacy of MSeA and MSeC vs. SeMet and characterize and validate key mechanistic biomarkers such as VEGF suppression for anti-angiogenesis and AR and PSA suppression for inhibition of androgen signaling. We expect to provide valuable efficacy and biomarker data to guide the design of future clinical translational studies with methyl-Se with greater prostate specific targeting actions. They will also be insightful for predicting and interpreting the outcomes of the SELECT study. Narrative: The results from these studies will provide valuable in vivo efficacy and biomarker data to guide the design of future human clinical trials for methyl selenium for prostate cancer chemoprevention. They will also be instructive for predicting and interpreting the outcomes of the ongoing selenium cancer prevention trials.