Chemoprevention of Head & Neck Cancer Using Controlled Release Polymers

描述(由申请人提供)： 超过50%的头颈部鳞状细胞癌(HNSCC)尽管进行了多种治疗，但仍会复发。由于局部治疗失败导致HNSCC的发病率和死亡率，确定有效的治疗方法以防止局部复发具有显著提高患者存活率的潜力。一种已被证明在前列腺癌和脑癌管理中有效的干预策略是使用可生物降解的聚合物植入物。虽然聚合物植入物提供了药理优势，但治疗效果高度依赖于包埋剂的疗效和可能的协同作用。我们建议评估三种天然化合物的衍生物：N-乙酰半胱氨酸(NAC)、内皮抑素和冷冻干燥黑树莓的水-乙醇提取物RO-ET。我们实验室的研究已经确定了NAC、内皮抑素和RO-ET抑制HNSCC致瘤表型的一些机制。NAC是一种替代前肽，可抑制基底膜降解明胶酶-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原肌素微丝结合，并抑制HNSCC的迁移和侵袭。Ro-ET对HNSCC细胞具有多种化学预防作用，包括减少血管内皮生长因子的释放、抑制一氧化氮合酶、启动细胞凋亡和诱导分化。我们假设所选择的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。这项应用的研究目的是：1)确定有效的药物剂量水平和评估药物组合的协同或可能的拮抗作用(Aim 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(Aim 1.b)，3)进行药代动力学分析并确定抑制HNSCC异种移植瘤形成的治疗能力(Aim 2)公共卫生相关性：头颈癌是一个重要的世界性健康问题，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防癌化合物，用于放置在控释载体中，用于植入手术部位，以防止局部治疗失败和抑制新癌症的发展。

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.