Chemoprevention of Oral Dysplasia by Black Raspberries

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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.