Chemopreventive Agent-Responsive Genes in Oral Cancer

描述(由申请人提供)：癌症化学预防被定义为联合或单独使用天然或合成试剂来抑制、延迟或逆转致癌过程，被公认为癌症研究的一个非常有前途的领域。许多流行病学研究表明，经常食用新鲜水果和蔬菜与降低癌症风险之间存在很强的相关性。在以食品为基础的癌症化学预防方法中，重点是在整个食品中使用复杂的预防性药物混合物来抑制多种致癌过程的可能性。为了支持这一方法，已经进行了几项临床前动物研究，证明黑树莓对化学诱导的呼吸道肿瘤的发展具有显著的化学预防活性，包括口腔、食道和结肠。虽然这种化学预防现象在癌症的动物模型中很明显，但黑树莓对人类癌症发展的化学预防潜力仍未得到研究。目前的建议基本上是翻译性质的，并努力将这种水果的化学预防评估扩展到人类口腔癌的问题。我们的初步研究表明，冻干黑树莓提取物(LBR)能显著抑制人口腔鳞状细胞癌细胞的体外增殖，提示LBR成分在体内化学预防口腔癌是可能的。因此，我们假设LBR将调节与关键生物学途径相关的关键基因的表达，这可能最终导致致癌过程的抑制、延迟或逆转。我们将首先确定黑树莓处理体外培养的人类口腔癌细胞后全球基因表达谱的变化(特定目标1)，然后通过1B期研究(特定目标2)确定黑树莓在体内调节原代人类口腔癌细胞类似基因表达谱的能力。这些新的研究将首次检验一种天然食品对人类口腔肿瘤发生的化学预防和分子效应。此外，这些数据将提供一个适当的基础，未来将在手术后患者或出现癌前病变的患者中进行使用LBR或其他针对反应基因的化学预防药物的化学预防研究。

DESCRIPTION (provided by applicant): Cancer chemoprevention is defined as the use of natural or synthetic agents, in combination or alone, to inhibit, delay, or reverse the carcinogenic process and is recognized as a very promising area of cancer research. Numerous epidemiological studies have shown the strong correlation between frequent consumption of fresh fruits and vegetables and a decreased cancer risk. With a food-based approach to cancer chemoprevention, emphasis is placed on the potential for complex mixtures of preventive agents in whole food to inhibit multiple processes of carcinogenesis. In support of this approach, several preclinical animal studies have been conducted that demonstrate the remarkable chemopreventive activity of black raspberries on chemically-induced aerodigestive tract tumor development, including oral, esophagus, and colon. While this chemopreventive phenomenon is striking in animal models of cancer, the chemopreventive potential of black raspberries on human cancer development remains unstudied. The present proposal is fundamentally translational in nature and strives to extend the chemopreventive assessment of this fruit to the problem of human oral cancer. Preliminary studies by us have shown that an extract of lyophilized black raspberries (LBR) dramatically inhibits the in vitro proliferation of cells derived from a human oral squamous cell carcinoma, suggesting that the chemoprevention of oral cancer by LBR components in vivo is possible. We therefore hypothesize that LBR will modulate the expression of critical genes associated with key biological pathways which may ultimately result in the inhibition, delay or reversal of the carcinogenic process. We will first identify changes in the global gene expression profiles in response to black raspberry treatment of human oral cancer cells in vitro (Specific Aim 1) and then determine the ability of black raspberries to modulate similar gene expression profiles in primary human oral cancer cells in vivo through a Phase 1B study (Specific Aim 2). These novel studies will be the first to examine the chemopreventive and molecular effects of a natural food product on human oral tumorigenesis. Additionally, these data will provide a suitable foundation from which future chemopreventive studies using LBR or other chemopreventive agents that target responsive genes will be conducted in post-surgical patients or those presenting with premalignant lesions.