Chemoprevention of Lung Cancer with Anti-tumor B

简介（由申请人提供）：抗肿瘤B (anti - tumor B，简称ATB)，又称曾生平，是一种由苦参、蓼、夏枯草、短尾Sonchus brachyotus、Dictambus dasycarpus、薯蓣等六种植物组成的复方中草药。先前的临床研究表明，ATB对人类食管癌和肺癌具有显著的化学预防作用。我们的初步数据表明，在p53显性阴性和/或Ink4a/Arf杂合缺失的a/ J小鼠中，ATB在苯并(a)芘诱导的肺癌发生中起有效的化学预防作用。虽然用ATB治疗的所有基因型小鼠都显示出肺癌多样性和肿瘤负荷的显著降低，但在具有所有三种遗传改变（Kras2、p53和Ink4A）的动物中，ATB表现出增强的抑制作用。我们假设ATB可以在突变小鼠模型中预防化学诱导的肺腺癌，这种突变小鼠模型具有人类肺癌中常见的遗传变化，并且ATB及其活性成分的化学预防作用部分是通过抑制AP-1抑制细胞增殖介导的。因此，我们提出以下具体目标：1)通过分离和体外筛选鉴定ATB的关键活性成分；2)利用肺癌小鼠体内模型测定选定的关键活性成分的疗效；3) ATB及其有效成分的药代动力学和生物制药特性；4)抗肿瘤B在肺癌化学预防中的作用机制及关键活性成分的研究。这一建议是及时和重要的，原因如下。首先，正在进行的ATB对人类肺癌的化学预防临床试验需要对其疗效和机制进行严格的临床前表征。其次，我们将使用一种新开发的肺腺癌小鼠模型，该模型具有在人类肺癌中观察到的组织病理学特征和遗传改变（激活的癌基因和灭活的肿瘤抑制基因）。第三，我们将对ATB的有效成分进行全面的化学分离和药代动力学表征。本研究结果将为ATB作为肺癌化学预防药物的临床试验提供坚实的基础。此外，本提案的结果也将为活性抑制成分及其如何影响肺癌发生过程提供重要的见解。

DESCRIPTION (provided by applicant): Antitumor B (ATB), also known as Zeng Sheng Ping, is a Chinese herbal mixture composed of six plants including Sophora tonkinensis, Polygonum bistorta, Prunella vulgaris, Sonchus brachyotus, Dictambus dasycarpus, and Dioscorea bulbifera. Previously, clinical studies have shown a significant chemopreventive efficacy of ATB against human esophageal and lung cancers. Our preliminary data indicate that ATB act as an effective chemopreventive agent of lung cancer in benzo(a)pyrene-induced lung carcinogenesis in A/J mice harboring a dominant-negative p53 and/or heterozygous deletion of Ink4a/Arf. While mice with all genotypes treated with ATB displayed a significant reduction in lung cancer multiplicity and tumor load, ATB exhibited an enhanced inhibitory effect in animals harboring all three genetic alterations (Kras2, p53, and Ink4A). We hypothesized that ATB will prevent chemically induced lung adenocarcinoma in a mutant mouse model with genetic changes commonly seen in human lung cancers, and the chemopreventive effect of ATB and its active components is, in part, mediated by inhibition of cell proliferation via inhibition of AP-1. Accordingly, we propose the following specific aims: 1) Identification of key active components of ATB via fractionation and in vitro screening assays; 2) Determination of the efficacy of selected key active components using in vivo mouse models of lung cancer; 3) Pharmacokinetic and biopharmaceutical characterization of ATB and its active components; and 4) Investigation of mechanisms of action of anti-tumor B and key active components in chemoprevention against the lung cancers. This proposal is timely and significant for the following reasons. Firstly, the ongoing chemoprevention clinical trial of ATB against lung cancer in humans requires rigorous preclinical characterization of its efficacy and mechanism(s). Secondly, we will use a newly developed mouse models of lung adenocarcinomas that share both histopathological features and genetic alterations (activated oncogenes and inactivated tumor suppressors) observed in human lung cancer. And thirdly, we will conduct comprehensive chemical fractionation and pharmacokinetic characterizations of ATB's active components. The results from this proposal will provide a solid foundation for clinical trials of ATB as a lung cancer chemopreventive agent. Furthermore, the results from this proposal will also provide significant insights on the active inhibitory components and how they affect lung carcinogenesis process.