Chemoprevention of Lung Cancer with Anti-tumor B

说明(申请人提供)：抗肿瘤B(ATB)，又称增生平，是由山豆、虎杖、夏枯草、短梗、白鲜皮、山药等6种植物组成的中草药混合物。此前，临床研究表明ATB对人类食道癌和肺癌具有显著的化学预防效果。我们的初步数据表明，在苯并(A)芘诱导的肺癌发生中，ATB是一种有效的肺癌化学预防药物。A/J小鼠携带显性阴性P53和/或Ink4a/Arf杂合缺失。虽然ATB治疗的所有基因类型的小鼠表现出肺癌多样性和肿瘤负荷的显著降低，但ATB在具有所有三种基因改变(Kras2、P53和Ink4a)的动物中表现出增强的抑制作用。我们假设ATB可以预防化学诱导的小鼠肺腺癌，这种突变的小鼠在人类肺癌中常见的基因改变，而ATB及其活性成分的化学预防作用部分是通过抑制AP-1来抑制细胞增殖。因此，我们提出了以下具体目标：1)通过分级和体外筛选方法鉴定ATB的关键活性成分；2)通过在体小鼠肺癌模型确定选定的关键活性成分的有效性；3)ATB及其活性成分的药代动力学和生物药学特性；以及4)研究抗肿瘤B和关键活性成分在化学预防肺癌中的作用机制。由于以下原因，这项提议是及时和重要的。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(S)。其次，我们将使用一种新开发的肺腺癌小鼠模型，该模型既有组织病理学特征，也有人类肺癌中观察到的遗传变化(激活的癌基因和失活的肿瘤抑制基因)。第三，我们将对ATB的活性成分进行全面的化学分级和药代动力学表征。这一建议的结果将为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，这一建议的结果还将为有效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.