Chemoprevention of Oral Dysplasia by Black Raspberries

描述（由申请人提供）：尽管努力改善治疗，口腔鳞状细胞癌（SCC）患者的五年生存率仍然令人沮丧的低。显然，早期检测结合局部干预策略，如口腔鳞状细胞癌发生前的化学预防，可以显着改善临床结果。口腔是人类化学预防试验的最佳部位，因为这些组织可以进行视觉监测。此外，口腔组织适合局部应用化学预防剂，这显著增加了靶部位的治疗剂浓度。我们实验室最近的研究表明，黑树莓在体外和体内水平上都具有化学预防特性。在大鼠和仓鼠模型系统中，冻干黑树莓的饮食管理成功地抑制了致癌作用。此外，黑树莓提取物处理的永生化人口腔角质形成细胞显示促血管生成和促炎分子的增殖和表达减少，同时保持与对照培养物相当的活力。这些数据表明，黑树莓的抗肿瘤作用反映了启动终末分化和/或凋亡信号通路的能力。我们的第一阶段人体临床试验也证实，高剂量的冻干黑树莓的饮食管理是良好的耐受性在人类。总的来说，这些数据意味着黑树莓是非常有前途的药物，用于人类临床化学预防试验。我们假设，使用生物粘附凝胶局部递送冻干黑树莓（FBR）将预防复发，抑制进展并诱导口腔上皮发育不良消退。将通过预处理和处理后的人活检中的以下实验参数评估冻干黑树莓局部应用对人口腔上皮发育不良病变的影响：ii）与癌前病变相关的分子生物标志物的表达[DNA倍性、增殖指数、促血管生成细胞因子（VEGF）的表达]，iii）与正常成熟（恢复到二倍体DNA含量）、终末分化（Ioricrin和fillagrin）和凋亡（caspase-3，调节的核碎裂）相关的分子生物标志物的表达。该实验设计（治疗前和治疗后组织的比较）允许每例患者作为其自身的内部对照。

DESCRIPTION (provided by applicant): Despite efforts to improve therapy, five year survival rates for patients with oral squamous cell carcinoma (SCC) remain discouragingly low. Clearly, early detection combined with local intervention strategies such as chemoprevention prior to oral SCC development could dramatically improve clinical outcomes. The oral cavity is an optimal site for a human chemoprevention trial, as these tissues can be visually monitored. Also, oral tissues are amenable to topical applications of chemopreventive agents, which markedly increases the therapeutic agent concentrations at the target site. Recent studies from our laboratories have demonstrated that black raspberries possess chemopreventive properties at both the in vitro and in vivo levels. Dietary administration of lyophilized black raspberries successfully inhibited carcinogenesis in both rat and hamster model systems. In addition, black raspberry extract treated immortalized human oral keratinocytes show a reduction in both proliferation and expression of pro-angiogenic and pro-inflammatory molecules while retaining comparable viabilities as control cultures. These data suggest that black raspberries' antitumorigenic effects reflect an ability to initiate terminal differentiation and/or apoptotic signaling pathways. Our Phase I human clinical trials have also confirmed that dietary administration of high dosages of lyophilized black raspberries is well tolerated in humans. Collectively, these data imply that black raspberries are highly promising agents for human clinical chemoprevention trials. We hypothesize that local delivery of freeze-dried black raspberries (FBR), using a bioadhesive gel, will prevent recurrence, inhibit progression and induce regression of oral epithelial dysplasia. The effects of local application of freeze-dried black raspberries on dysplastic lesions of human oral epithelium will be assessed by the following experimental parameters in pretreated and post-treated human biopsies: i) clinical appearance and light microscopic diagnosis, ii) expression of molecular biomarkers associated with premalignancy [DNA ploidy, indices of proliferation, expression of the proangiogenic cytokine (VEGF)], iii) expression of molecular biomarkers associated with normal maturation (return to diploid DNA content), terminal differentiation (Ioricrin and fillagrin) and apoptosis (caspase-3, regulated nuclear fragmentation). This experimental design (comparison of pretreatment and post-treatments tissues) permits each patient to serve as their own internal control.