Inhibition of Oral Tumorigenesis by Antitumor B

项目总结： 抗肿瘤B(ATB)，也被称为增生平，是根据现代GMP标准制造的片剂。它 蕴含以下六种中草药的提取物：山豆根、何首乌、夏枯草 Vergaris，Sonchus brachyotus，DicTamnus dasycarpus，和Dioscorea Bulbifera。此前，临床研究已经 显示ATB对人食管鳞癌的显著化学预防作用 口腔癌。在口腔白斑患者的随机临床试验中，使用ATB(4片，3次 每天8-12个月)减少了68%的患者的口腔病变大小，而在 安慰剂对照组(P&lt；0.01)，表明ATB可能是一种有效的预防药物 人类患口腔癌的风险。我们发现ATB抑制化学诱导的口腔鳞状细胞癌(通过 ~60%)，并确定了几种能够抑制口腔癌细胞的关键活性化合物 扩散。我们发表的研究还表明，在口腔组织中发现了几种关键的活性化合物 可能与ATB的化学预防作用有关。然而，目前还不清楚是否有关键的活性成分 (KAc)，称为ATB-KAcα，其富含三种活性化合物(即，独断胺， 秦皮酮和马钱子)，因此在化学上更好地定义用于QA/QC目的，将具有更强的 对口腔癌变的抑制作用优于阿替丁。我们将使用4NQO诱导的口腔癌小鼠 模型和“机会之窗(WOO)”试验方法确定ATB-KACα及其 药效学(PD)反应和药代动力学(PK)特性和疗效的生物标志物。我们 假设口服化学定义更好的ATB-KAcα可以显著提高对 在小鼠模型中预防口腔癌的发生，并将具有理想的PK特性和生物标志物 在老鼠和人类身上都有反应。目标1将进行植物化学和药代动力学表征 ATB-KAcα，并开发PD/PK模型来描述它们的疗效和生物标记物反应。目标2将进行 小鼠口腔癌化学预防研究确定α对小鼠口腔癌发生和发展的影响 以确定新的生物标记物。AIM 3将在新发疾病患者中进行ATB、ATB-KACα或安慰剂的WOO试验 被诊断为口腔癌。这一建议是及时和重要的，因为拟议的WOO审判是重要的一步 为未来人类第二阶段研究开发ATB-KACα，填补以下知识空白 人类和配对的小鼠模型中的生物标记物。此外，我们还将测量PD和PK ATB-KAcα在Woo试验中的反应，并建立PK/PD模型，以进一步加深我们对 未来第二阶段人体研究所需的必要剂量。

Project Summary: Antitumor B (ATB), also known as Zeng Sheng Ping, is a tablet made according to modern GMP standards. It contains the extracts of following six Chinese medicinal herbs: Sophora tonkinensis, Polygonum bistorta, Prunella vulgaris, Sonchus brachyotus, Dictamnus dasycarpus, and Dioscorea bulbifera. Previously, clinical studies have shown significant chemopreventive efficacy of ATB against human esophageal squamous cell carcinomas and oral cancers. In a randomized clinical trial in patients with oral leukoplakia, treatment with ATB (4 tablets, 3 times per day for 8–12 months) reduced the size of oral lesions in 68% of the patients versus 17% of the patients in the placebo control group (P < 0.01), indicating that ATB may be a potent preventive agent against the development of oral cancer in humans. We found that ATB inhibited chemically induced oral squamous cell carcinomas (by ~60%) in mice and identified several key active compounds that are capable of inhibiting oral cancer cell proliferation. Our published study also showed that several key active compounds were found in the oral tissues and likely contributed to the chemoprevention effects of ATB. However, it is unknown if a key active component (KAC), called ATB-KACα which is enriched with 50% or more of three active compounds (i.e., dictamine, fraxinellone and maackiain) and therefore better chemically defined for QA/QC purposes, will have a stronger efficacy against oral carcinogenesis than ATB. We will use both the 4NQO-induced oral carcinogenesis mouse model and a “window of opportunity (WOO)” trial approach to determine the efficacy of ATB-KACα along with its pharmacodynamic (PD) responses and pharmacokinetic (PK) properties and biomarkers of efficacy. We hypothesize that oral administration of a better chemically defined ATB-KACα can significantly increase efficacy in preventing oral carcinogenesis in mouse models and will have the desirable PK properties and biomarker responses in both mice and humans. Aim 1 will perform phytochemical and pharmacokinetic characterizations of ATB-KACα and develop a PD/PK model to describe their efficacy and biomarker responses. Aim 2 will conduct mouse oral cancer chemoprevention studies to determine the efficacy of ATB-KACα on oral carcinogenesis and to identify novel biomarkers. Aim 3 will perform a WOO trial of ATB, ATB-KACα, or placebo in patients with newly diagnosed oral cancer. This proposal is timely and significant because the proposed WOO trial is important step for the development of ATB-KACα for future human phase II studies by filling the knowledge gap between biomarkers in humans and those in the matched mouse models. In addition, we will measure the PD and PK responses of ATB-KACα in the WOO trial and develop a PK/PD model to further enhance our understanding the necessary dose needed for future phase II human studies.