Chemoprevention of Head & Neck Cancer Using Controlled Release Polymers

项目摘要/摘要R01 CA129609A2 超过50%的头颈部鳞状细胞癌(HNSCC)尽管有多种模式，但仍会复发 心理治疗。由于局部治疗失败导致HNSCC的发病率和死亡率，确定 预防局部复发的有效治疗有可能显著改善患者状况 生死存亡。一种干预战略，事实证明，这在管理两者中都是有效的 前列腺癌和脑癌，是使用可生物降解的聚合物植入物。而聚合物 植入物提供了药理优势，治疗效果高度依赖于 包埋剂的有效性和可能的协同作用。我们建议对三个方面进行评估 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 冷冻干燥黑覆盆子提取物，RO-ET。我们实验室的研究表明 NAC、Endostatin和RO-ET抑制HNSCC的一些机制 致瘤表型。NAC作为一种替代前肽，抑制激活和 基底膜降解明胶酶的功能，基质金属蛋白酶-9。我们的数据还显示， 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诱导了多种化学预防作用 HNSCC细胞，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。我们假设被选中的特工 会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HNSCC肿瘤发生的关键途径。本应用的研究目标是 要：1)确定有效的药剂剂量水平并评估药剂组合的协同作用或 可能的拮抗作用(目标1.A.)，2)评估化学预防药物的效果 HNSCC肿瘤外植体中肿瘤-间质相互作用的研究(目标1.b)，3)进行药代动力学 分析和确定抑制HNSCC异种移植瘤形成的治疗能力(目的 2)。

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).