Chemoprevention of oral cancer: model studies

虽然通过戒烟和适度饮酒进行初级预防应该是控制头颈癌最成功的策略，但评价补充方法（如化学预防）作为实现这一目标的手段非常重要。维生素A（类维生素A）、β-胡萝卜素、维生素E和硒的天然和合成类似物在头颈癌的化学预防研究中有报道。 文献数据似乎支持维生素和矿物质的混合物的化学预防功效上级单一药剂的概念。 缺乏数据表明，由于大规模的化学预防剂干预试验，口腔癌和其他头颈癌的发病率和死亡率有所降低。 在这个时候，它似乎还为时过早，建议补充特定的化学预防剂作为预防头颈癌的常规策略。 因此，本研究的基础是系统地确定相关药物（单独和联合）的疗效;最初，在明确的动物模型试验中，并描述病因学和预防中涉及的作用机制。我们证明了lacZ转基因小鼠在研究中的实用性，这些研究涉及由合成的4-硝基喹啉-N-氧化物（4-NQO）以及烟草及其热解产物（4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮[NNK]和苯并（a）芘[BaP]）中存在的致癌物引发口腔致癌作用。 我们还证明，在几个器官（包括口腔组织）中补充合成有机硒化合物（1，4-亚苯基双（亚甲基）硒氰酸酯，p-XSC）或维生素E和C的饮食可以在不同程度上抑制诱变，该系统可用于评估其他化学预防剂。 此外，我们已经表明，在F344大鼠中，p-XSC可以抑制舌肿瘤并阻断由4-NQO诱导的细胞增殖。此外，在我们实验室以及其他实验室中获得的结果清楚地表明，硒化合物的一种形式，而不是硒本身，在癌症化学预防中至关重要。 根据我们的初步结果和文献报道的结果，我们假设以p-XSC或天然存在的Se-甲基硒代半胱氨酸（MSC）形式的硒、维生素A和E的组合应该被证明是非常有前途的口腔癌化学预防的鸡尾酒。具体而言，该混合物将抑制氧化损伤、细胞增殖和考克斯-2活性;这将导致诱导细胞凋亡和抑制肿瘤发生。 为了验证我们的假设，我们的具体目标是：1。 确定硒（MSC和p-XSC）、维生素A和E单独和联合使用对lacZ转基因小鼠口腔中4-NQO和BaP诱导的诱变的抑制作用。 2. 确定最有效的混合物（目标1中开发）对4-NQO和BaP分别在雄性F344大鼠和雌性B6 C3 F小鼠中诱导的舌肿瘤发展的化学预防效力。 3. 检查鸡尾酒对大鼠和小鼠舌中关键中间生物标志物（细胞增殖、氧化、DNA损伤、COX活性和细胞凋亡）的影响。 该项目的结果将为在未来的口腔癌化学预防临床试验中使用最有效的鸡尾酒的可行性提供见解。

Although primary prevention by tobacco use cessation and by moderation in alcohol intake should be the most successful strategy for control of head and neck cancer, the evaluation of complementary approaches, such as chemoprevention, is very important as a means toward achieving this goal. Natural and synthetic analogs of vitamin A (retinoids), beta-carotene, vitamin E and selenium are featured in the reported studies of chemoprevention of head and neck cancer. Literature data appear to support the notion that the chemopreventive efficacy of a mixture of vitamins and minerals is superior to a single agent. Data showing a reduction in the incidence and mortality rates of oral and other head and neck cancers as a result of large-scale intervention trials with chemopreventive agents are lacking. At this time, it appears premature to suggest supplementation of specific chemopreventive agents as a routine strategy to prevent head and neck cancer. Therefore, the basis of the present investigation is to systematically determine the efficacy of relevant agents, individually and in combination; initially, in well-defined animal model assays and with delineation of the mechanisms of action involved in etiology and prevention. We demonstrated the utility of the lacZ transgenic mouse for investigations involving initiation pf carcinogenesis of the oral cavity by synthetic 4-nitroquinoline-N-oxide (4-NQO), as well as carcinogens present in tobacco and its pyrolysis products (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK] and benzo(a)pyrene [BaP]). We also demonstrated that a diet supplemented with a synthetic organoselenium compound (1,4-phenylenebis(methylene)selenocyanate, p-XSC)) or with vitamin E and C in several organs, including oral tissues, can inhibit mutagenesis to varying extents and the system can be used to evaluate other chemopreventive agents. In addition, we have shown that, in F344 rats, p-XSC can inhibit tumors of the tongue and block the cell proliferation induced by 4-NQO. Furthermore, results obtained in our laboratory, as well as in others, clearly demonstrate that a form of selenium compound, not selenium per se, is critical in cancer chemoprevention. On the basis of our preliminary results and those reported in the literature, we hypothesize that the combination of selenium in the form of p-XSC or the naturally-occurring Se-methylselenocysteine (MSC), vitamin A, and E should prove to be highly promising cocktail for chemoprevention of cancer of the oral cavity. Specifically, this cocktail will inhibit oxidative damage, cell proliferation and COX-2 activity; this will result in induction of apoptosis and inhibition of tumorigenesis. To test our hypothesis, our specific aims are: 1. To determine the inhibition of mutagenesis induced by 4-NQO and BaP in the oral cavity of the lacZ transgenic mouse by selenium (MSC and p-XSC), vitamin A, and E individually and in combination. 2. To determine the chemopreventive efficacy of the most effective cocktail (developed in Aim 1) against the development of tumors of the tongue induced by 4-NQO and BaP in male F344 rats, and in female B6C3F mice, respectively. 3. To examine the effect of the cocktail on critical intermediate biomarkers (cell proliferation, oxidative, DNA damage, COX-activities, and apoptosis) in the tongue of the rat and mouse. The results of this project will provide insights regarding the feasibility of using the most effective cocktail in future clinical trials toward chemoprevention of oral cancer.