Molecular Correlates of Soy in Humans

描述（由申请人提供）：大豆是一种有前途的癌症化学预防剂。大豆消费者似乎具有较低的转移性前列腺癌（PCa）的发病率。我们已经表明，大豆成分，染料木黄酮，酪氨酸激酶抑制剂，通过增加PCa细胞粘附，而在高浓度下，它抑制PCa细胞生长，以拮抗转移行为。我们最近完成了一个单剂量的第一阶段的研究，在人类，证明染料木素调节细胞内酪氨酸磷酸化（或细胞信号）的血细胞。为了进一步了解大豆在体内的作用，我们正在实施一项II期临床试验，即将进行根治性前列腺切除术的PCa患者将随机接受2 mg金雀异黄素/kg/天的治疗（或不治疗），以评估组织的中间生物标志物。我们假设用大豆衍生的染料木黄酮治疗将拮抗人前列腺细胞的转移行为，将对细胞信号传导具有长期影响，并且还将影响前列腺细胞的存活和生长。我们提出了以下具体目标：#1：确定大豆是否拮抗人类的转移行为。转移性前列腺细胞可以通过逆转录聚合酶链反应（RT/PCR）扩增PSA特异性RNA来检测。 我们将测量大豆减少外周血和手术野血中循环转移性前列腺细胞的能力。此外，将通过前列腺组织的定量图像分析来测量对细胞形态的处理相关影响（对细胞粘附影响的替代指标）。#2：评估大豆对体内细胞信号传导途径的影响。比较大豆处理和对照前列腺组织，将在粘附相关基因（FAK和内皮糖蛋白）中以及通过基于基因阵列的基因谱分析测量基因表达的变化。此外，将通过测量血细胞蛋白酪氨酸磷酸化随时间的变化来寻求对体内细胞信号传导的长期影响。#3：确定大豆是否调节体内前列腺细胞的存活和生长。 研究将检查大豆对一组与前列腺细胞活力和生长相关的生物标志物的影响，包括凋亡指数，细胞相关PCNA，p27表达，血清PSA和血清睾酮。

DESCRIPTION (provided by applicant): Soy is a promising cancer chemopreventive agent. Soy consumers appear to have a lower incidence of metastatic prostate cancer (PCa). We have shown that a soy constituent, genistein, a tyrosine kinase inhibitor, acts to antagonize metastatic behavior by increasing PCa cell adhesion, while at high concentrations it inhibits PCa cell growth. We recently completed a single dose phase I study in humans, demonstrating that genistein modulates intracellular tyrosine phosphorylation (or cell signaling) of blood cells. To further understand soy's in vivo effects, we are implementing a phase II clinical trial in which patients with PCa who are to have radical prostatectomy will be randomized to treatment (or not) with 2 mg genistein/kg/day, allowing evaluation of tissue for intermediate biomarkers. We hypothesize that treatment with soy-derived genistein will antagonize metastatic behavior of human prostate cells, will have long term effects on cell signaling, and will also effect prostate cell survival and growth. We propose the following specific aims: #1 : Determine whether soy antagonizes metastatic behavior in humans. Metastatic prostate cells can be detected by amplifying PSA specific RNA by reverse transcriptase polymerase chain reaction (RT/PCR). We will measure soy's ability to decrease circulating metastatic prostate cells in peripheral blood, as well as in operative field blood. In addition, treatment-related effects upon cellular morphology (a surrogate measure of effect upon cell adhesion) will be measured by quantitative image analysis of prostate tissue. #2: Evaluate effects of soy upon cell signaling pathways in vivo. Comparing soy-treated and control prostate tissue, changes in gene expression will be measured in adhesion-related genes (FAK and endoglin), as well as by gene array-based gene profiling. In addition, long-term effects upon cell signaling in vivo will be sought by measuring changes in protein-tyrosine phosphorylation of blood cells over time. #3: Determine whether soy modulates prostate cell survival and growth in vivo. Investigations will examine soy's effects upon a panel of biomarkers related to prostate cell viability and growth, including apoptotic index, cell-associated PCNA, p27 expression, serum PSA and serum testosterone.