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: 8867171
• 负责人: Susan R Mallery
• 金额: $ 31.81万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8867171
• 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; 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; 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; psychological trauma; 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.

描述（由申请人提供）：