Evaluation of bioadhesive berry gels for oral cancer chemoprevention

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令人沮丧地低。早期发现结合局部干预策略，如口腔鳞状细胞癌发生前的化学预防，可以显著改善临床结果。然而，以前进行的口腔化学预防试验的结果并不是很有希望。值得注意的是，以前的大多数口服化学预防试验都是系统地给药。对于有针对性的疾病治疗，局部给药方法相对于全身给药有几个优势，包括直接将治疗相关的浓度输送到皮损部位。我们实验室最近的研究表明，黑树莓在体外和体内都具有预防癌症的特性。在动物模型中，饮食中添加冷冻干燥的黑覆盆子(FBR)成功地抑制了食道癌和面颊囊癌。同样，体外研究表明，FBR和黑树莓提取物都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。对于有癌前状态的人，口腔上皮异型增生，化学预防可能在他们的余生中是必要的。因此，确定在皮损部位提供最大浓度的制剂中提供的无毒、有效的药物对于改善患者预后是必要的。根据我们的结果，我们假设浆果凝胶通过减弱促炎和促增殖途径而产生化学预防作用，同时刺激分化和凋亡等生长调节机制。我们还推测口腔粘膜的植物化学代谢调节局部应用的母体化合物的化学预防效果。具体目的1研究将评估优化的浆果凝胶配方影响：1)活性物质的组织生成，2)促血管生成分子的产生，以及3)口腔表面上皮细胞的增殖、分化和凋亡指数。针对特定目的提出的研究2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，这种凝胶含有自然产生的抗癌化合物，以确定凝胶对口腔组织的化学预防(癌症预防)能力。 口腔癌在美国仍然是一个严重的健康问题。即使对那些可以治愈的人来说，必要的手术也是虚弱的，往往会毁容。这些研究将测试生物黏附凝胶的效果，其中包含自然产生的抗癌化合物，以确定凝胶对人类口腔组织外植体的化学预防(抗癌)能力。

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.