Molecular Correlates of Soy in Humans

描述(申请人提供)：大豆是一种很有前途的癌症化学预防药物。大豆消费者的转移性前列腺癌(PCA)发病率似乎较低。我们已经证明，大豆成分金雀异黄素，一种酪氨酸激酶抑制剂，通过增加PCa细胞的粘附性而发挥抗转移行为的作用，而在高浓度时，它抑制PCa细胞的生长。我们最近在人类身上完成了一项单剂量I期研究，证明了染料木素调节血细胞内酪氨酸磷酸化(或细胞信号)。为了进一步了解大豆的体内效应，我们正在实施一项II期临床试验，在该试验中，将接受根治性前列腺切除术的前列腺癌患者随机接受(或不接受)2毫克染料木素/公斤/天的治疗，以便评估组织中的中间生物标志物。我们假设大豆衍生金雀异黄素的治疗将对抗人类前列腺细胞的转移行为，将对细胞信号产生长期影响，并将影响前列腺细胞的生存和生长。我们提出了以下具体目标：#1：确定大豆是否对抗人类的转移行为。通过逆转录聚合酶链式反应(RT/PCR)扩增PSA特异性RNA可以检测转移性前列腺癌细胞。我们将测量大豆减少外周血和手术现场血中循环转移的前列腺癌细胞的能力。此外，与治疗相关的对细胞形态的影响(细胞黏附影响的替代测量)将通过前列腺组织的定量图像分析来衡量。#2：评估大豆对体内细胞信号通路的影响。对比大豆处理的和对照的前列腺组织，黏附相关基因(FAK和endoglin)以及基于基因阵列的基因图谱将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。调查将考察大豆对一组与前列腺细胞存活和生长相关的生物标记物的影响，包括细胞凋亡指数、细胞相关的增殖细胞核抗原、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.