Chemoprevention of Oral Dysplasia by Black Raspberries

黑树莓化学预防口腔发育不良

基本信息

批准号：
6762326
负责人：
Susan R Mallery
金额：
$ 20.18万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-06 至 2006-07-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：尽管努力改善治疗，但口服鳞状细胞癌（SCC）患者的五年存活率仍然令人沮丧。显然，早期检测与局部干预策略相结合，例如口服SCC发育前的化学预防策略可以大大改善临床结果。口腔是人类化学预防试验的最佳部位，因为可以在视觉上监测这些组织。同样，口腔组织适合化学预防剂的局部应用，这显着增加了目标部位的治疗剂浓度。我们实验室的最新研究表明，黑色覆盆子在体外和体内均具有化学预防特性。冻干的黑色覆盆子的饮食给药成功地抑制了大鼠和仓鼠模型系统中的癌变。此外，黑色覆盆子提取物处理过的永生的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均降低，同时保留了可比较的生存能力作为对照培养物。这些数据表明，黑色覆盆子的抗肿瘤效应反映了启动末端分化和/或凋亡信号通路的能力。我们的I期人类临床试验还证实，饮食中的高剂量高剂量的黑色覆盆子在人类中的耐受性良好。总的来说，这些数据表明，黑色覆盆子是人类临床化学预防试验的高度有希望的药物。我们假设使用生物粘附性凝胶局部递送冻干的黑色覆盆子（FBR）将防止复发，抑制进展并诱导口腔上皮发育不良的回归。 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）与正常成熟（返回二倍体DNA含量），末端分化（Ioricrin和Fillagrin）和凋亡（caspase-3，调节的核碎片）相关的分子生物标志物的表达。这种实验设计（对预处理和治疗后组织的比较）允许每个患者作为自己的内部控制。