Evaluation of locally-delivered fenretinide and black raspberries for oral cancer

局部给药芬维A胺和黑树莓治疗口腔癌的评价

• 批准号: 8392351
• 负责人: Susan R Mallery
• 金额: $ 33.12万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392351
• 关键词: Address; Adverse effects; Affect; Binding; Biochemical; Biopsy; Body part; Carcinoma; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Research; Data; Databases; Development; Disease; Dose; Drug Formulations; Drug Kinetics; Economic Burden; Electron Transport; Environment; Enzymes; Esthetics; Evaluation; Event; Excision; Face; Fenretinide; Freeze Drying; Gel; Gene Expression Regulation; Growth; Human; In Vitro; Inflammation; Inflammation Mediators; Intraepithelial Neoplasia; Lesion; Malignant - descriptor; Malignant Neoplasms; Mediating; Metabolism; Modality; Modeling; Molecular; Mus; Nature; Operative Surgical Procedures; Oral; Oral cavity; Oral mucous membrane structure; Outcome; Oxidation-Reduction; PTGS2 gene; Pathology; Pathway interactions; Patients; Pharmaceutical Chemistry; Phenotype; Premalignant; Price; Production; Property; Proteins; Radiation; Raspberries; Recurrence; Regional Disease; Regulation; Reliance; Reporting; Research; Research Methodology; Research Personnel; Role; Schedule; Scheme; Signal Transduction; Site; Solid Neoplasm; Sulfhydryl Compounds; Survival Rate; System; Techniques; Testing; Therapeutic; Therapeutic Effect; Tissues; Topical application; Toxic effect; Trauma; Vitamin A; Xenobiotics; analog; angiogenesis; base; cancer chemoprevention; cell growth; cell growth regulation; chemotherapy; cytokine; disorder control; human data; in vivo; keratinocyte; malignant mouth neoplasm; metabolic abnormality assessment; mouth squamous cell carcinoma; oral lesion; preclinical study; prevent; programs; psychologic; public health relevance; response; socioeconomics; transcription factor; tumor; tumorigenic; uptake

DESCRIPTION (provided by applicant): Per the NCI database, approximately 39,400 new cases of oral squamous cell carcinoma (OSCC) and 7,900 deaths will occur in the U.S. during 2011. Despite extensive efforts, OSCC survival remains among the lowest for solid tumors in the U.S.-a fact which emphasizes the need for better outcomes via more effective OSCC chemoprevention. Previous OSCC chemoprevention trials, which relied upon systemic agent delivery, were largely unsuccessful. The limitations of systemic delivery, which include inability to achieve therapeutic levels at the target site and systemic toxicity, prompted us to develop formulations amenable for local agent delivery. In our pilot oral cancer chemopreventive trial, a topically applied bioadhesive freeze-dried black raspberry (BRB) gel regressed lesions of oral epithelial dysplasia (OED) without any deleterious side effects. For some OED lesions, however, the BRB gel was insufficient. We have subsequently developed a mucoadhesive fenretinide patch that delivers therapeutic levels of the synthetic vitamin A analogue, fenretinide, to oral mucosa. Patch-delivered fenretinide circumvents previously reported systemic toxicities and introduces a chemically distinct, highly promising chemopreventive to the locally delivered OSCC chemoprevention battery. Notably, a cytokine and inflammation-rich environment, which perturbs redox-mediated signaling and thiol dependent proteins, drives the progression of OED to overt OSCC. Furthermore, many cellular pathways modulated by BRB and fenretinide rely upon proteins that contain redox sensitive thiols. We therefore hypothesize that BRB's and fenretinide's abilities to modulate thiol dependent proteins responsible for redox- based signaling and growth regulation are integral to their chemopreventive efficacy. Accordingly, Specific Aims of this proposal are: 1) Investigate the effect of BRB and fenretinide on the regulation of oral keratinocyte growth and transition to the tumorigenic phenotype in vitro., 2) Optimize BRB and fenretinide local delivery formulations for oral cancer chemoprevention., 3) Study the efficacy, metabolism and pharmacokinetics of locally delivered BRB and fenretinide using two complementary murine models. Research methodology includes a variety of biochemical and molecular analyses (Aim 1), pharmaceutical chemistry techniques (Aim 2) and pathology, pharmacokinetics and metabolism studies (Aim 3). Based on their unique mechanisms of action, we anticipate that optimized combined BRB and fenretinide dosing schemes will elicit the best responses-e.g. increased keratinocyte terminal differentiation and diminished proinflammatory and angiogenic cytokine production. In vivo, therapeutic effects will manifest as decreased progression (primary) or tumor size (secondary) due to diminished angiogenesis and keratinocyte and endothelial mobility. Public Health Relevance: Despite costly and extensive research, oral cancer remains a deadly disease. These studies introduce a fresh approach-act before the development of oral cancer by use of locally-delivered cancer- preventing agents to treat precancerous lesions in the mouth without affecting other parts of the body. PUBLIC HEALTH RELEVANCE: Despite costly and extensive research, oral cancer remains a deadly disease. These studies introduce a fresh approach-act before the development of oral cancer by use of locally-delivered cancer-preventing agents to treat precancerous lesions in the mouth without affecting other parts of the body.

描述（由申请人提供）： 根据NCI数据库，大约39,400例口腔鳞状细胞癌（OSCC）和7,900例死亡的新病例在2011年期间将发生7,900例死亡。尽管进行了广泛的努力，OSCC的生存仍然是美国A事实最低的事实之一，强调了通过更有效的OSCC化学化学剂进行更好的现象，这是一种强调，这是ASC的最低效果。以前依赖于系统性剂传递的OSCC化学预防试验在很大程度上没有成功。系统性输送的局限性包括无法在目标部位达到治疗水平和全身毒性，这促使我们开发了适合当地代理交付的配方。在我们的试点口腔癌化学预防试验中，一项局部应用的生物粘附性冷冻干燥的黑色覆盆子（BRB）凝胶会回归口服上皮性发育不良（OED）的病变，而没有任何有害的副作用。但是，对于某些OED病变，BRB凝胶不足。随后，我们开发了一种粘粘性灰粘蛋白贴片，该贴剂将合成维生素的治疗水平递送为类似物芬雷丁蛋白，以口服粘膜。斑块递送的芬雷丁代表先前报道了全身毒性，并向当地传递的OSCC化学预防电池引入了化学不同的，高度有希望的化学预防。值得注意的是，氧化还原介导的信号传导和硫醇依赖性蛋白的细胞因子和炎症环境驱动OED向明显的OSCC的发展。此外，许多由BRB和Fenretinide调节的细胞途径依赖于含有氧化还原敏感硫醇的蛋白质。因此，我们假设BRB和Fenretinide调节负责基于氧化还原的信号传导和生长调控的硫醇依赖性蛋白的能力与其化学预防效力不可或缺。因此，该提案的具体目的是：1）研究BRB和芬替丁对口服角质形成细胞生长的调节的作用，并过渡到体外的肿瘤性表型。，2）优化BRB和Fenretinide局部局部递送对口服癌症的疗效，研究的效率，3）研究。使用两个互补的鼠模型。研究方法包括各种生化和分子分析（AIM 1），药物化学技术（AIM 2）以及病理学，药代动力学和代谢研究（AIM 3）。根据其独特的作用机制，我们预计优化的BRB和Fenretinide剂量方案将引起最佳响应。角质形成细胞末端分化增加，并减少促炎和血管生成细胞因子的产生。在体内，由于血管生成减少以及角质形成细胞和内皮迁移率，治疗作用将表现为减少进展（原发性）或肿瘤大小（次要）。公共卫生相关性：尽管进行了昂贵且广泛的研究，但口腔癌仍然是一种致命的疾病。这些研究通过使用局部递送的癌症来介绍口腔癌发展前的新方法，以防止药物治疗口腔中的癌前病变，而不会影响身体的其他部位。 公共卫生相关性： 尽管进行了昂贵且广泛的研究，但口腔癌仍然是一种致命的疾病。这些研究通过使用局部保留癌症预防剂来治疗口腔中的癌前病变，而不会影响身体的其他部位，从而引入了口腔癌发展之前的新方法。