Antitumor and chemopreventive activity of the Ecuadorian plant extract BIRM

描述(由申请者提供)：恶性疾病患者通常使用不具特色的药物或膳食补充剂。大量使用未经测试的配方，既提供了机会，也带来了危险。BIRM是厄瓜多尔的一种口服溶液，是一种由安第斯品种的白花龙葵L开发的膳食补充剂，在美洲被广泛食用，用于治疗包括前列腺癌和乳腺癌在内的多种疾病，没有任何明显的毒性。BIRM在前列腺癌模型上的初步实验室研究表明，它具有很强的细胞毒性抗肿瘤活性，包括诱导细胞凋亡、细胞周期停滞、降低雄激素受体水平和下调促生存基因。在大鼠Dunning mat LyLu模型和人前列腺癌移植瘤模型中口服BIRM显示出BIRM的化学预防和抗转移活性。它降低了肿瘤发生率(75%)、肿瘤生长(50%)和转移(63%)。这些观察结果为进一步研究BIRM作为化学预防膳食补充剂的使用提供了基础。将在该项目中检验的主要假设是，BIRM是一种无毒、化学预防的天然产品，具有延缓肿瘤生长、进展和复发的潜力。该应用的主要目的是在前列腺癌转基因模型中建立BIRM的化学预防和抗转移活性，目的是确定其安全性和有效性，用于临床对照试验。目的1在转基因小鼠前列腺癌(TRAMP)模型上建立BIRM的最小有效剂量、最佳有效剂量和最大耐受量。此外，BIRM的化学预防和抗肿瘤活性将通过两种不同的转基因模型进行研究，这两种模型通过雄激素非依赖性机制(GVT-15模型)或通过有条件地敲除前列腺中的肿瘤抑制基因(PTEN loxP/loxpPBCre-4)而发生前列腺癌。在目标2中，将通过描绘各自信号通路的分子特征的变化来研究BIRM诱导细胞凋亡、细胞周期停滞和雄激素受体降解的分子机制。在目标3中，将在两个人类前列腺癌原位移植模型LNCaP和LAPC-4中评估BIRM单独或与标准化疗联合使用预防激素抵抗型前列腺癌的效果，这两个模型显示出不同的雄激素受体分子形式。相关性：这项研究将建立BIRM的安全性和毒性概况，并确定BIRM这一复杂的天然产品是否具有1.已证实的预防前列腺癌的化学预防功效，以及2.已证实的癌症疗法的有效性是否被BIRM增强或显著降低。这项研究也应该为这种化学预防药物的进一步开发(如果有的话)提供一个理论基础，即口腔癌和其他恶性肿瘤的临床试验。

DESCRIPTION (provided by applicant): Patients with malignant diseases commonly consume poorly characterized medicine or dietary supplements. Extensive use of untested formulations, provide both opportunities and danger. BIRM, an Ecuadorian oral solution, is a dietary supplement developed from the Andean variety of Solanum dulcamara L, which is widely consumed in the Americas for a variety of diseases, including prostate and breast cancers, without any noted toxicity. Initial laboratory studies of BIRM on prostate cancer models showed strong cytotoxic antitumor activity, including induction of apoptosis, cell-cycle arrest, reduction in androgen receptor levels and down-regulation of pro-survival genes. Oral dosing of BIRM in a rat Dunning MAT LyLu model and in human prostate cancer xenografts showed chemopreventive and antimetastatic activities of BIRM. It decreased tumor incidence (75%), tumor growth (50%) and metastasis (63%). These observations provide the basis for further investigation into the use of BIRM as a chemopreventive dietary supplement. The main hypothesis, to be tested in this project, is that BIRM is a non-toxic, chemopreventive, natural product with the potential to retard tumor growth, progression and recurrence. The main objective of this application is to establish the chemopreventive and antimetastatic activity of BIRM in transgenic models of prostate cancer with the goal of establishing its safety and efficacy for use in controlled clinical trials. In Aim 1, the minimum effective dose, optimum effective dose and maximum tolerated dose of BIRM will be established in the TRAMP (transgenic adenocarcinoma of the mouse prostate) model. In addition, the chemopreventive and antitumor activities of BIRM will be investigated using two distinct transgenic models that develop prostate tumor by either an androgen-independent (GvT-15 model) mechanism or by the conditional knock-out of a tumor suppressor gene (PTEN) in the prostate (PTEN loxp/loxpPBCre-4). In Aim 2, the molecular mechanism of BIRM induced apoptosis, cell cycle arrest and androgen receptor degradation will be investigated by delineating the alterations in the molecular signatures of respective signaling pathways. In Aim 3, the efficacy of BIRM either alone, or in combination with standard chemotherapy, will be evaluated for preventing the emergence of hormone-refractory prostate cancer in two human prostate cancer orthotopic xenograft models, LNCaP and LAPC-4, which demonstrate distinct molecular forms of androgen receptor. Relevance: This study will establish safety and toxicity profiles of BIRM and determine whether BIRM, a complex natural product, has 1. a proven chemopreventive efficacy against prostate cancer and 2. if the efficacy of proven cancer therapies are enhanced or significantly compromised by BIRM. This study should also provide a rationale for further development (if any), of this chemopreventive agent, i.e., clinical trials for orostate cancer and other malignant cancers.