Molecular Correlates of Soy in Humans

简介（申请人提供）：大豆是一种很有前途的癌症化学预防剂。大豆消费者似乎有转移性前列腺癌（PCa）的发病率较低。我们已经证明大豆成分染料木素，一种酪氨酸激酶抑制剂，通过增加PCa细胞粘附来对抗转移行为，而高浓度时它抑制PCa细胞生长。我们最近完成了一项人类单剂量I期研究，证明染料木素调节血细胞的细胞内酪氨酸磷酸化（或细胞信号传导）。为了进一步了解大豆在体内的作用，我们正在进行一项II期临床试验，在该试验中，接受根治性前列腺切除术的PCa患者将随机接受（或不接受）2mg染料木黄酮/kg/天的治疗，以评估组织中的中间生物标志物。我们假设用大豆来源的染料木素治疗会拮抗人类前列腺细胞的转移行为，对细胞信号传导有长期影响，也会影响前列腺细胞的存活和生长。我们提出以下具体目标：#1：确定大豆是否能对抗人类的转移行为。通过逆转录聚合酶链反应（RT/PCR）扩增PSA特异性RNA，可以检测转移性前列腺细胞。我们将测量大豆降低外周血和手术野血中循环转移性前列腺细胞的能力。此外，治疗对细胞形态的相关影响（对细胞粘附影响的替代测量）将通过前列腺组织的定量图像分析来测量。#2：评估大豆对体内细胞信号通路的影响。比较大豆处理和对照前列腺组织，将通过黏附相关基因（FAK和内啡肽）以及基于基因阵列的基因谱来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 .确定大豆是否在体内调节前列腺细胞的存活和生长。研究将检验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、细胞相关的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.