Antitumor and chemopreventive activity of the Ecuadorian plant extract BIRM

描述（申请人提供）：恶性疾病患者通常服用特征不佳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，是从安第斯山脉的Solanum dulcamara L品种中开发出来的一种膳食补充剂，在美洲被广泛用于治疗各种疾病，包括前列腺癌和乳腺癌，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显示出强细胞毒性抗肿瘤活性，包括诱导细胞凋亡、细胞周期停滞、雄激素受体水平降低和促生存基因下调。在大鼠Dunning MAT LyLu模型和人前列腺癌异种移植物中口服BIRM显示出BIRM的化学预防和抗转移活性。肿瘤发生率（75%）、肿瘤生长（50%）和转移（63%）降低。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用途提供了基础。在本项目中要检验的主要假设是，BIRM是一种无毒的、化学预防性的天然产物，具有延缓肿瘤生长、进展和复发的潜力。本申请的主要目的是确定BIRM在前列腺癌转基因模型中的化学预防和抗转移活性，目的是确定其用于对照临床试验的安全性和有效性。在目标1中，将在TRAMP（小鼠前列腺转基因腺癌）模型中确定BIRM的最小有效剂量、最佳有效剂量和最大耐受剂量。此外，BIRM的化学预防和抗肿瘤活性将使用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（GvT-15模型）机制或通过前列腺中肿瘤抑制基因（PTEN）的条件性敲除（PTEN loxp/loxpPBCre-4）形成前列腺肿瘤。在目标2中，BIRM诱导的细胞凋亡，细胞周期阻滞和雄激素受体降解的分子机制将通过描绘各自信号通路的分子特征的改变来研究。在目标3中，将在两种人前列腺癌原位异种移植模型LNCaP和LAPC-4中评价BIRM单独或与标准化疗联合用于预防难治性前列腺癌出现的疗效，这两种模型显示了雄激素受体的不同分子形式。相关性：本研究将建立BIRM的安全性和毒性特征，并确定BIRM（一种复杂的天然产物）是否具有1。经证实的对前列腺癌的化学预防功效，以及2. BIRM是否增强或显著损害了已证实的癌症治疗的疗效。本研究还应提供进一步开发（如有）该化学预防剂的基本原理，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.