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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.

项目总结:

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.