Evaluation of bioadhesive berry gels for oral cancer chemoprevention

生物粘附浆果凝胶用于口腔癌化学预防的评价

• 批准号: 7382405
• 负责人: Susan R Mallery
• 金额: $ 21.8万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-07 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382405
• 关键词: Address; Adverse effects; Affect; Animal Model; Anthocyanins; Anthracenes; Apoptosis; Apoptotic; Attenuated; Benzo(a)pyrene; Berry; Biological Markers; Carcinoma; Cell Line; Cheek structure; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Chemoprevention; Clinical Research; Clinical Trials; Complication; Conduct Clinical Trials; Cytoprotection; Daily; Data; Development; Disease; Disease Management; Disease regression; Dose; Drug Formulations; Drug Kinetics; Early Diagnosis; Epoxy Compounds; Esophageal; Esophagus; Ethanol; Evaluation; Event; Foundations; Freeze Drying; Future; Gel; Gene Expression; Generations; Glycol; Goals; Grant; Growth; Hamsters; Health; Human; Human Volunteers; In Vitro; Individual Differences; Induction of Apoptosis; Inflammation; Intervention; Intraepithelial Neoplasia; Investigation; Knowledge; Laboratories; Lesion; Life; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mesocricetus auratus; Metabolism; Methods; Mucositis; Nitrosamines; Operative Surgical Procedures; Oral; Oral Surgical Procedures; Oral cavity; Oral mucous membrane structure; Outcome; Oxidation-Reduction; Parents; Pathway interactions; Patients; Personal Satisfaction; Persons; Phase; Phosphotransferases; Phytochemical; Placebo Control; Precancerous Conditions; Premalignant; Production; Property; Protein Isoforms; Public Health; Raspberries; Rattus; Recurrence; Relative (related person); Resistance; Reverse Transcriptase Polymerase Chain Reaction; Saliva; Series; Site; Squamous cell carcinoma; Staging; Surface; Survival Rate; Testing; Therapeutic Index; Time; Tissues; Topical application; Toxic effect; Transcription Factor AP-1; Treatment Protocols; Urine; Vitamin A; Water; Week; activating transcription factor; angiogenesis; anthracene; attenuation; base; cell growth; clinically relevant; cyanidin; cytokine; day; design; dosage; embryo cell; fighting; human NOS2A protein; human tissue; improved; in vivo; indexing; interest; keratinocyte; malignant mouth neoplasm; mouth squamous cell carcinoma; nitrosobenzylmethylamine; oral carcinogenesis; oral cavity epithelium; oral lesion; oral tissue; outcome forecast; peripheral blood; prevent; tumorigenesis

DESCRIPTION (provided by applicant): Despite concerted efforts to improve therapy, five year survival rates for patients with advanced stage oral squamous cell carcinoma (oral SCC) remain discouragingly low. Early detection combined with strategies for local intervention, such as chemoprevention prior to oral SCC development, could dramatically improve clinical outcomes. Results of previously conducted oral cavity chemoprevention trials, however, have not been highly promising. Notably, the majority of previous oral chemoprevention trials administered agents systemically. For targeted disease management, local delivery methods have several advantages relative to systemic administration that include delivery of therapeutically relevant concentrations directly to the lesional site. Recent studies from our laboratories have shown that black raspberries possess cancer preventing properties at both the in vitro and in vivo levels. Dietary administration of freeze-dried black raspberries (FBR) successfully inhibited both esophageal and cheek pouch carcinoma in animal models. Likewise, in vitro studies have shown both FBR and black raspberry extracts regulate cell growth by a variety of mechanisms that include scavenging of reactive species, initiation of apoptosis and induction of differentiation. For persons with the premalignant condition, oral epithelial dysplasia, chemoprevention will likely be necessary for the remainder of their lives. Therefore, identification of nontoxic, effective agents delivered in formulations that provide maximal concentrations at the lesional site, is necessary to improve patient prognosis. Based on our results we hypothesize that berry gels elicit their chemopreventive effects by attenuation of proinflammatory and proproliferative pathways while concurrently stimulating growth regulatory mechanisms such as differentiation and apoptosis. We also speculate that oral mucosal phytochemical metabolism modulates chemopreventive effects of the topically applied parent compounds. Specific Aim 1 studies will evaluate the ability of optimized berry gel formulations to affect: 1) tissue generation of reactive species, 2) production of proangiogenic molecules, and 3) proliferation, differentiation and apoptotic indices of surface oral epithelium. Studies proposed for Specific Aim 2 will evaluate the capacity for human oral mucosa to: 1) metabolize selected FBR phenolic compounds, 2) modulate chemopreventive properties of FBR parent compounds. Public health relevance: These studies will test bioadhesive gels, which contain naturally occurring cancer fighting compounds to determine the gels' chemopreventive (cancer preventing) abilities on oral tissues. Oral cancer remains a significant health problem in the U.S. Even for those persons who can be cured, the necessary surgery is debilitating and often disfiguring. These studies will test the effects of bioadhesive gels, which contain naturally occurring cancer fighting compounds, to determine the gels' chemopreventive (cancer fighting) abilities on explants of human oral mouth tissues.

描述（由申请人提供）： 尽管共同努力改善治疗，晚期口腔鳞状细胞癌（口腔 SCC）患者的五年生存率仍然低得令人沮丧。早期检测与局部干预策略相结合，例如口腔鳞状细胞癌发生前的化学预防，可以显着改善临床结果。然而，之前进行的口腔化学预防试验的结果并不乐观。值得注意的是，大多数先前的口服化学预防试验都是全身给药。对于靶向疾病管理，局部递送方法相对于全身给药具有多个优点，包括将治疗相关浓度直接递送至病变部位。我们实验室的最新研究表明，黑树莓在体外和体内水平上都具有预防癌症的特性。在动物模型中，通过膳食摄入冻干黑树莓 (FBR) 可以成功抑制食道癌和颊囊癌。同样，体外研究表明 FBR 和黑树莓提取物通过多种机制调节细胞生长，包括清除活性物质、启动细胞凋亡和诱导分化。对于患有癌前病变、口腔上皮发育不良的人来说，化学预防可能是他们余生所必需的。因此，有必要确定以在病变部位提供最大浓度的制剂形式递送的无毒、有效的药物，以改善患者的预后。根据我们的结果，我们假设浆果凝胶通过减弱促炎和增殖途径来引发化学预防作用，同时刺激分化和细胞凋亡等生长调节机制。我们还推测口腔粘膜植物化学代谢调节局部应用的母体化合物的化学预防作用。具体目标 1 研究将评估优化的浆果凝胶配方影响以下方面的能力：1) 活性物质的组织生成，2) 促血管生成分子的生成，以及 3) 口腔表面上皮的增殖、分化和凋亡指数。针对特定目标 2 提出的研究将评估人类口腔粘膜的能力：1）代谢选定的 FBR 酚类化合物，2）调节 FBR 母体化合物的化学预防特性。公共卫生相关性：这些研究将测试生物粘附凝胶，其中含有天然存在的抗癌化合物，以确定凝胶对口腔组织的化学预防（癌症预防）能力。 在美国，口腔癌仍然是一个重大的健康问题。即使对于那些可以治愈的人来说，必要的手术也会使人衰弱，而且常常毁容。这些研究将测试含有天然抗癌化合物的生物粘附凝胶的效果，以确定凝胶对人类口腔组织外植体的化学预防（抗癌）能力。