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Inhibition of Oral Tumorigenesis by Antitumor B

抗肿瘤 B 抑制口腔肿瘤发生

基本信息

批准号：
10516360
负责人：
MING HU
金额：
$ 47.14万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-08 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10516360
关键词：
A/J Mouse Aftercare Animal Model Antitumor Response Area Biological Biological Availability Biological Markers Blood Circulation Cancer Model Cell Proliferation Chemicals Chemoprevention Chemopreventive Agent Chinese Chinese Herbs Clinical Clinical Research Clinical Trials Control Groups Development Dictamnus Dose Drug Kinetics Esophageal Squamous Cell Carcinoma Exposure to Future Goals Human In Vitro Incidence Knowledge Lesion Malignant neoplasm of esophagus Measures Medicinal Herbs Modernization Molecular Target Mouth Neoplasms Mus Newly Diagnosed Normal tissue morphology Oral Oral Administration Oral Leukoplakia Pathway interactions Patients Pharmacodynamics Phase Phase II Clinical Trials Phytochemical Placebo Control Placebos Plasma Polygonum Prevention trial Preventive Property Protocols documentation Prunella vulgaris Publishing Randomized Randomized Clinical Trials Research Project Grants Resected Saliva Sampling Sonchus Sophora Tablets Testing Time Tissues Transgenic Organisms United States Yam - dietary antitumor effect arm base cancer chemoprevention cohort design in vivo inhibitor insight liquid chromatography mass spectrometry malignant mouth neoplasm molecular marker mouse model mouth squamous cell carcinoma neoplastic cell novel marker oral carcinogenesis oral lesion oral tissue oral tumorigenesis patient population pharmacodynamic model pharmacokinetic model pharmacokinetics and pharmacodynamics phase 2 study pre-clinical predictive marker prevent response response biomarker transcriptome sequencing tumor

项目摘要

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.

项目概要：抗肿瘤B（AT B），又称增升平，是按照现代GMP标准生产的片剂。它含有六种中草药的提取物：越南槐、拳参、夏枯草 vulgaris、短叶苦苣菜（Sonchus bracyotus）、白藓（Dictamnus dasycarpus）和黄连菜（Escherichia bulbifera）。此前，临床研究显示ATB对人食管鳞状细胞癌具有显著的化学预防功效，口腔癌在一项口腔白斑患者的随机临床试验中，ATB（4片，3次）治疗每日1次，持续8-12个月）使68%的患者的口腔病变尺寸减小，而对照组中仅17%的患者安慰剂对照组（P < 0.01），提示ATB可能是一种有效的预防药物口腔癌的发病率我们发现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增殖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，目前尚不清楚是否有一个关键的活性成分， (KAC)，称为ATB-KAC α，其富含50%或更多的三种活性化合物（即，竹黄胺，秦皮酮和maackiain），因此更好地化学定义为QA/QC目的，将具有更强的抗口腔癌作用优于ATB。我们将使用4 NQO诱导的口腔癌小鼠模型和“机会窗口（WOO）”试验方法，以确定ATB-KACα沿着其药效学（PD）反应和药代动力学（PK）特性和功效的生物标志物。我们假设口服化学成分更好的ATB-KAC α可显著增加预防小鼠模型中的口腔癌发生，并具有理想的PK特性和生物标志物小鼠和人类的反应。目的1将进行植物化学和药代动力学表征 ATB-KACα并开发PD/PK模型以描述其疗效和生物标志物反应。目标2将进行小鼠口腔癌化学预防研究，以确定ATB-KACα对口腔癌发生的疗效，来鉴定新的生物标志物。目标3将在新发诊断为口腔癌。这项建议是及时和重要的，因为拟议的WOO试验是重要的一步通过填补以下方面的知识空白，开发用于未来人体II期研究的ATB-KAC α 在人类和那些在匹配的小鼠模型的生物标志物。此外，我们将测量PD和PK WOO试验中ATB-KACα的反应，并开发PK/PD模型，以进一步增强我们对ATB-KACα的理解。未来II期人体研究所需的必要剂量。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pharmacokinetic Characterization and Bioavailability Barrier for the Key Active Components of Botanical Drug Antitumor B (ATB) in Mice for Chemoprevention of Oral Cancer.

DOI：
10.1021/acs.jnatprod.1c00501
发表时间：
2021-09-24
期刊：
JOURNAL OF NATURAL PRODUCTS
影响因子：
5.1
作者：
Bui, Dinh;Yin, Taijun;Duan, Shengnan;Wei, Bo;Yang, Peiying;Wong, Stuart J.;You, Ming;Singh, Rashim;Hu, Ming
通讯作者：
Hu, Ming

Chemoprevention of Lung Cancer with a Combination of Mitochondria-Targeted Compounds.

DOI：
10.3390/cancers14102538
发表时间：
2022-05-21
期刊：
CANCERS
影响因子：
5.2
作者：
Zhang, Qi;Xiong, Donghai;Pan, Jing;Wang, Yian;Hardy, Micael;Kalyanaraman, Balaraman;You, Ming
通讯作者：
You, Ming

Mitochondria-targeted atovaquone promotes anti-lung cancer immunity by reshaping tumor microenvironment and enhancing energy metabolism of anti-tumor immune cells.

线粒体靶向的阿托伐醌通过重塑肿瘤微环境和增强抗肿瘤免疫细胞的能量代谢来促进抗肺癌免疫。

DOI：
10.1002/cac2.12500
发表时间：
2024
期刊：
Cancer communications (London, England)
影响因子：
0
作者：
Xiong,Donghai;Yin,Zheng;Huang,Mofei;Wang,Yian;Hardy,Micael;Kalyanaraman,Balaraman;Wong,StephenT;You,Ming
通讯作者：
You,Ming

Pharmacokinetic and Metabolic Profiling of Key Active Components of Dietary Supplement Magnolia officinalis Extract for Prevention against Oral Carcinoma.