PREVENTION OF PANCREATIC CANCER BY CALORIE RESTRICTION

胰腺癌是癌症死亡的第五大原因， 美国的 它的预后是令人沮丧的， 预防这种疾病。 该实验室先前的研究表明， 在仓鼠胰腺导管癌的延迟喂养略有减少 卡路里摄入量 拟议的研究将直接调查 的热量限制对胰腺癌的影响， 2-（氧代丙基）亚硝胺（BOP）诱导的胰腺癌模型中的 叙利亚仓鼠。 这种胰腺癌模型与 人类胰腺癌 我们发现， 凝集素L-PHA（来自红芸豆）和LEL（来自番茄），以及 肿瘤细胞膜和细胞内A血型抗原抗体 胰腺导管癌分离的细胞系与 正常胰腺 这种变化代表了 与肿瘤发生和转移相关的寡糖结构 表型。 我们早期关于热量限制和皮肤的研究 致癌作用表现为蛋白激酶C（PKC）的抑制 来自喂食卡路里限制的小鼠皮肤的表皮细胞中的活性 节食。 这一观察结果可能对抑制癌症是重要的， 饮食限制，因为PKC已被确定为 佛波醇酯肿瘤促进剂和作为重要的细胞增殖 和分化途径。 这项建议的具体目标是： 1)确定分级热量限制对胰腺癌的影响 在仓鼠模型中使用BOP作为引发剂的致癌作用。 饮食 限制在90%、80%和60%的控制热量摄入将被喂养 从BOP开始后一周开始，直至 study. 仓鼠将根据速率饲养100-120周 癌症的发展。 2)评估热量限制的影响 仓鼠体内肿瘤的转移潜能 胰腺 细胞表面低聚糖的表达与 将在正常的肿瘤中检查转移表型， 在受限的仓鼠中。 3)热量限制对 蛋白激酶C同工酶水平和细胞及亚细胞分布 将通过胰腺中的免疫组织化学来确定。 仓鼠 将预先喂食控制和热量限制饮食6-10周， PKC水平的比较。 拟议的研究将证明， 热量限制可以预防胰腺癌的发生， 肿瘤的转移潜能。 我们的结果也将 评估热量是否能抑制胰腺癌的发生 限制可能是由于导管细胞PKC减少所致。

Pancreatic cancer is the fifth leading cause of death by cancer in the United States. Its prognosis is dismal and little is known regarding prevention of this disease. Previous studies from this laboratory showed a delay in pancreatic ductular cancer in hamsters fed a slightly reduced calorie intake. Proposed studies will directly investigate the influence of calorie restriction on pancreatic cancer in the bis- 2(oxopropyl)nitrosamine (BOP) induced model of pancreatic cancer in the syrian hamster. This model of pancreatic cancer is particularly relevant to human pancreatic cancer. We have found an increase in the binding of the lectins L-PHA (from red kidney beans) and LEL (from tomatoes), and antibodies to Blood Group A antigens in tumor cell membranes and in cell lines isolated from pancreatic ductular carcinomas in comparison with normal pancreas. Such changes represent increased expression of oligosaccharide structures associated with the tumorigenic and metastatic phenotype. Our earlier investigations on calorie restriction and skin carcinogenesis demonstrated an inhibition of protein kinase C (PKC) activity in epidermal cells from the skin of mice fed calorie restricted diets. This observation may be important in the inhibition of cancer by dietary restriction because PKC has been identified as the receptor of the phorbol ester tumor promoters and as important in cell proliferation and differentiation pathways. The specific aims of this proposal are: 1) Determine the influence of graded calorie restriction on pancreatic carcinogenesis in the hamster model using BOP as the initiator. Diets restricted to 90%, 80% and 60% of the control calorie intake will be fed beginning one week following initiation with BOP until the end of the study. Hamsters will be held for 100-120 weeks depending upon the rate of development of cancer. 2) Assess the influence of calorie restriction on the metastatic potential of the tumors developing in the hamster pancreas. The expression of cell-surface oligosaccharides associated with the metastatic phenotype will be examined in tumors in normal and in restricted hamsters. 3) The influence of calorie restriction on protein kinase C isozyme levels and cellular and subcellular distribution will be determined by immune histochemistry in the pancreas. Hamsters will be prefed control and calorie restricted diets for 6-10 weeks before comparison of PKC levels. The proposed studies will demonstrate if calorie restriction can prevent pancreatic carcinogenesis and reduce the metastatic potential of tumors that do develop. Our results will also assess if the inhibition of pancreatic carcinogenesis by calorie restriction could be caused by reduction in duct cell PKC.