Chemoprevention of Head & Neck Cancer Using Controlled Release Polymers

头部化学预防

基本信息

批准号：
8197246
负责人：
Susan R Mallery
金额：
$ 30.19万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197246
关键词：
1-Phosphatidylinositol 3-Kinase Acetylcysteine Address Adjuvant Affect American Angiogenesis Inhibitors Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apoptosis Appearance Basement membrane Binding Cells Chemoprevention Chemopreventive Agent Cicatrix Clinical Clinical Trials Collagen Type XVIII Combined Modality Therapy Connective Tissue Critical Pathways Cytoprotection Data Development Diagnosis Dose Drug Delivery Systems Drug Kinetics Encapsulated Endostatins Epithelial Epithelial Cells Epithelium Ethanol Excision Freeze Drying Gel Gelatinase B Gelatinases Gene Expression Genes Glutathione Goals Growth Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Health Human Immunotherapy Implant Individual Induction of Apoptosis Injectable Integrins Intervention Laboratories Left Location Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of prostate Matrix Metalloproteinases Mediating Methods Microfilaments Molecular Morbidity - disease rate Nitric Oxide Synthase Nude Mice Operative Surgical Procedures Outcome Oxidation-Reduction Oxidative Stress PTGS2 gene Parents Pathway interactions Patient Noncompliance Patients Persons Pharmaceutical Preparations Phenotype Phosphotransferases Polymers Premalignant Prodrugs Property Prostate Protein S Radiation Radiation therapy Raspberries Reactive Nitrogen Species Recurrence Regimen Research Signal Transduction Site Source Staging Stromal Neoplasm Sulfhydryl Compounds Surface Surgical complication System Therapeutic Therapeutic Agents Tissues Transglutaminases Treatment Efficacy Treatment Failure Trocars Tumor Tissue Tumorigenicity Vascular Endothelial Growth Factors Vascular blood supply Water Wound Healing Xenograft procedure abstracting aggressive therapy angiogenesis base biodegradable polymer cancer recurrence caspase-3 cell motility chemotherapy cohort compliance behavior controlled release cytokine design effective therapy gene therapy human NOS2A protein implantation improved in vivo local drug delivery migration mortality nitrosative stress oral lesion poly(lactide)prevent proMMP-2 public health relevance synergism therapy development treatment site tumor tumor xenograft tumorigenesis tumorigenic

项目摘要

Project Summary/Abstract R01 CA129609A2 Over 50% of head and neck squamous cell carcinomas (HNSCC) recur despite multimodal therapy. As local treatment failures drive HNSCC morbidity and mortality, identification of effective treatments to prevent local recurrence has the potential to dramatically improve patient survival. One intervention strategy, which has proven effective in the management of both prostate and brain cancers, is the use of biodegradable polymer implants. While polymer implants provide a pharmacologic advantage, therapeutic benefits are highly dependent upon efficacy and possible synergism of the encapsulated agents. We propose to evaluate three derivatives of natural compounds: N-acetylcysteine (NAC), endostatin and a water-ethanol extract of freeze dried black raspberries, RO-ET. Studies in our laboratories have characterized some of the mechanisms by which NAC, endostatin and RO-ET suppress the HNSCC tumorigenic phenotype. NAC serves as a surrogate propeptide and inhibits activation and function of the basement membrane degrading gelatinase, MMP-9. Our data also show that the established angiostatic agent endostatin binds to HNSCC tropomysin microfilaments and inhibits HNSCC migration and invasion. RO-ET elicited a variety of chemopreventive effects in HNSCC cells that included reduction in VEGF release, inhibition of nitric oxide synthase, initiation of apoptosis and induction of differentiation. We hypothesize that the selected agents will reduce intracellular levels of reactive species, inhibit redox mediated gene expression and suppress pathways critical for HNSCC tumorigenesis. The research aims of this application are to: 1) determine effective agent dosing levels and evaluate agent combinations for synergistic or possible antagonistic effects (Aim 1.a.), 2) evaluate the effects of the chemopreventive agents on tumor-stromal interactions in HNSCC tumor explants (Aim 1.b.), 3) conduct pharmacokinetic analyses and determine therapeutic abilities to suppress HNSCC xenograft tumorigenesis (Aim 2). Public health relevance: Head and neck cancer is a significant worldwide health problem, and a major reason for treatment failure is cancer recurrence. The goal of these studies is to identify effective cancer-preventing compounds for placement in controlled release delivery vehicles for implantation at the surgery site to prevent local treatment failures and inhibit development of new cancers.

项目摘要/摘要 R01 CA129609A2 尽管采用多模式治疗，仍有超过 50% 的头颈鳞状细胞癌 (HNSCC) 复发治疗。由于局部治疗失败会导致 HNSCC 发病率和死亡率，因此需要识别预防局部复发的有效治疗有可能显着改善患者的病情生存。一种干预策略，已被证明对管理两者均有效前列腺癌和脑癌的治疗，是利用可生物降解的聚合物植入物。而聚合物植入物提供药理优势，治疗效果高度依赖于胶囊化药物的功效和可能的协同作用。我们建议评估三个天然化合物的衍生物：N-乙酰半胱氨酸（NAC）、内皮抑素和水-乙醇冻干黑树莓提取物，RO-ET。我们实验室的研究表明 NAC、内皮抑素和 RO-ET 抑制 HNSCC 的一些机制致瘤表型。 NAC 作为替代前肽并抑制激活和基底膜降解明胶酶 MMP-9 的功能。我们的数据还表明已确定的血管抑制剂内皮抑素与 HNSCC 原霉素微丝结合，抑制 HNSCC 迁移和侵袭。 RO-ET 在以下疾病中引发了多种化学预防作用 HNSCC 细胞包括减少 VEGF 释放、抑制一氧化氮合酶、细胞凋亡的启动和分化的诱导。我们假设所选的代理将降低细胞内活性物质的水平，抑制氧化还原介导的基因表达，抑制 HNSCC 肿瘤发生的关键途径。本申请的研究目的是目的： 1) 确定有效的药物剂量水平并评估药物组合的协同或可能的拮抗作用（目标 1.a.），2）评估化学预防药物的作用关于 HNSCC 肿瘤外植体中肿瘤-基质相互作用的研究（目标 1.b.），3) 进行药代动力学分析并确定抑制 HNSCC 异种移植肿瘤发生的治疗能力（目的 2）。公共卫生相关性：头颈癌是一个重大的全球健康问题，治疗失败的一个主要原因是癌症复发。这些研究的目标是确定用于控释递送的有效预防癌症化合物用于在手术部位植入的车辆，以防止局部治疗失败并抑制新癌症的发展。