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）正在测试硒（Se）单独或与维生素E联合使用的硒（SeMet）形式预防前列腺癌（PCa）的有效性，该试验在约32，400名北美男性中进行。 结果预计在十年内。 如果证实了积极的预防效果，使用这种形式的硒对公共卫生的影响是不言而喻的，这将为进一步的临床试验提供巨大的动力，以确定更有效的硒制剂，以实现更大的预防效益。 如果是否定的，那么寻求有效的硒剂就显得非常紧迫。 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，我们将它们统称为甲基硒）比硒蛋氨酸更有效的抗前列腺癌的过程，如抑制血管生成开关机制，诱导G1细胞周期停滞，减少AKT激活和诱导半胱天冬酶介导的凋亡。 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，这是至关重要的前列腺癌的发展。 此外，我们现在在初步研究中发现，每天口服MSeA和甲基硒代半胱氨酸（MSeC）对无胸腺裸鼠中的DU 145人PCa异种移植物生长产生剂量依赖性抑制，而相同剂量的SeMet则没有。 我们推测，甲基硒通过其广谱抗癌作用，通过抑制肿瘤血管生成，细胞周期阻滞和/或诱导半胱天冬酶介导的细胞凋亡，以及通过前列腺器官特异性抑制AR表达和信号传导，在体内预防PCa。 为了验证这一假设，我们提出了3个具体的目标，在雄激素依赖性（AD）和雄激素非依赖性（AI）PCa异种移植模型和TRAMP（转基因小鼠前列腺癌）原发性前列腺癌模型。 我们将确定MSeA和MSeC与SeMet的体内化学预防功效，并表征和验证关键的机制生物标志物，如VEGF抑制抗血管生成和AR和PSA抑制雄激素信号传导。 我们希望提供有价值的疗效和生物标志物数据，以指导未来的临床转化研究的设计与甲基硒与更大的前列腺特异性靶向行动。 他们还将对预测和解释SELECT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体临床试验的设计。 它们也将对预测和解释正在进行的硒预防癌症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.