Chemoprevention of Head & Neck Cancer Using Controlled Release Polymers

头部化学预防

• 批准号: 7753611
• 负责人: Susan R Mallery
• 金额: $ 31.35万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/7753611
• 关键词: 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; Matrix Metalloproteinases; Mediating; Methods; Microfilaments; Molecular; Morbidity - disease rate; Nitric Oxide Synthase; Nude Mice; Operative Surgical Procedures; Outcome; Oxidation-Reduction; PTGS2 gene; Parents; Pathway interactions; Patient Noncompliance; Patients; Persons; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Polymers; Premalignant; Prodrugs; Property; Prostate; Proteins; 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; 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）： 尽管采用多模式治疗，超过 50% 的头颈鳞状细胞癌 (HNSCC) 仍会复发。由于局部治疗失败会导致 HNSCC 的发病率和死亡率，因此确定有效的治疗方法来预防局部复发有可能显着提高患者的生存率。一种干预策略是使用可生物降解的聚合物植入物，已被证明对治疗前列腺癌和脑癌有效。虽然聚合物植入物具有药理学优势，但治疗效果很大程度上取决于封装药物的功效和可能的协同作用。我们建议评估三种天然化合物衍生物：N-乙酰半胱氨酸 (NAC)、内皮抑素和冻干黑树莓的水乙醇提取物 RO-ET。我们实验室的研究已经描述了 NAC、内皮抑素和 RO-ET 抑制 HNSCC 致瘤表型的一些机制。 NAC 作为替代前肽并抑制基底膜降解明胶酶 MMP-9 的激活和功能。我们的数据还表明，已建立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 HNSCC 细胞中引发多种化学预防作用，包括减少 VEGF 释放、抑制一氧化氮合酶、启动细胞凋亡和诱导分化。我们假设所选药物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并抑制对 HNSCC 肿瘤发生至关重要的途径。本申请的研究目的是：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) 评估化学预防药物对 HNSCC 肿瘤外植体中肿瘤-基质相互作用的影响（目标 1.b.），3) 进行药代动力学分析并确定抑制 HNSCC 异种移植物的治疗能力 肿瘤发生（目标 2） 公共健康相关性：头颈癌是一个重大的世界性健康问题，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有效的抗癌化合物，将其放置在控释递送载体中，植入手术部位，以防止局部治疗失败并抑制新癌症的发展。