Prevention of Oral Cancer by Strawberries with Selenium Assimilated in the Fruit

描述（由申请人提供）： 口腔癌占美国癌症的2.5%，是全球第六大常见癌症，五年生存率约为50%;在过去30年中，每年的死亡人数没有显著变化。由于这种高死亡率，而且目前的治疗方法相对无效，因此必须开发口腔癌的干预方法并在动物模型中进行测试。口腔癌的动物模型，仓鼠颊囊（HCP），已经表明，参与癌症过程的细胞和组织变化在人类和仓鼠之间是相似的。由于这些相似性，我们使用仓鼠口腔癌模型来证明黑树莓的化学预防活性，并将这项研究转化为Ib-IIa期人体临床试验。目前的申请扩展了由加州草莓委员会资助的正在进行的项目，其中冻干草莓（LS）被用于抑制口腔癌的形成和发展。在目前的建议中，我们将评估LS和硒对口腔癌的化学预防的综合作用，使用在水果形成过程中含有硒的草莓。将使用三种不同的协议。首先，在用化学致癌物处理HCP前一周开始，将给予仓鼠含有0%或10%粉末状LS或LS-硒（LS-Se）的AIN-76 A颗粒饲料（3X/周，持续8周）; LS和LS-Se喂养持续13周（完全化学预防方案）。在第二次和第三次中，HCP将用化学致癌物开始（3X/周，持续6-7周），并且在最后一次致癌物给药后48小时开始，仓鼠被给予含有0%或10%LS或LS-Se的AIN-76 A颗粒的饮食，或者用0%或10%LS或LS-Se局部处理3X/周（开始后方案）。对照动物仅接受AIN-76 A颗粒或溶剂载体。启动后实验将模拟类似于前烟草使用者的情况。我们预计，草莓粉将抑制肿瘤形成时，在饮食中给予致癌物治疗之前，期间或之后，因为我们已经观察到与黑树莓。此外，基于显示单独硒的化学预防活性的研究，我们证实用LS-Se治疗将导致化学预防活性的显著增强，并将抑制发育异常病变进展为明显的肿瘤。启动后实验的成功结果将导致在与人类消费相容的媒介物中使用LS或LS-Se在高风险人群中进行人类临床试验。

DESCRIPTION (provided by applicant): Cancers of the oral cavity account for 2.5% of cancers in the United States and are the sixth most common cancer worldwide with a five year survival of approximately 50%; the number of deaths per year has not significantly changed in the past 3 decades. Because of this high mortality rate and since present treatments are relatively ineffective, intervention methods for oral cancer must be developed and tested in animal models. An animal model of oral cancer, the hamster cheek pouch (HCP), has shown that cell and tissue changes that are involved in the cancer process are similar between humans and hamsters. Because of these similarities, we have used the hamster oral cancer model to demonstrate chemopreventive activity of black raspberries and have translated this research into Phase Ib-IIa human clinical trials. The current application expands an ongoing project funded by the California Strawberry Commission in which lyophilized strawberries (LS) are being used to inhibit formation and development of oral cancers. In the current proposal, we will evaluate the combined effect of LS and selenium on the chemoprevention of oral cancer using strawberries that have selenium incorporated during formation of the fruit. Three different protocols will be used. In the first, hamsters will be given a diet of AIN-76A pellets containing 0% or 10% powdered LS or LS-selenium (LS-Se) beginning one week prior to treatment of the HCP with a chemical carcinogen (3X/wk for 8 wks); LS and LS-Se feeding is continued through 13 wks (Complete Chemoprevention Protocol). In the second and third, HCP will be initiated with chemical carcinogen (3X/wk for 6-7 wks) and beginning 48 hrs after the last dose of carcinogen, hamsters are given a diet of AIN-76A pellets containing 0% or 10% LS or LS-Se or treated topically 3x/week with 0% or 10% LS or LS-Se (Post-initiation Protocols). Control animals receive only AIN- 76A pellets or solvent vehicle. The Post-initiation experiments will mimic a condition similar to that seen in former tobacco users. We anticipate that the strawberry powder will inhibit tumor formation when given in the diet before, during, or after carcinogen treatment, as we have observed with black raspberries. Further, based on studies showing chemopreventive activity of selenium alone, we posit that treatment with LS-Se will result in a significant enhancement of chemopreventive activity and will inhibit progression of dysplastic lesions into overt tumors. A successful outcome of the post-initiation experiments will lead to human clinical trials in high risk populations using LS or LS-Se in a vehicle compatible with human consumption.