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DIETARY MODIFICATION & PROMOTION OF LIVER CARCINOGENESIS

饮食调整

基本信息

批准号：
3167363
负责人：
HISASHI SHINOZUKA
金额：
$ 14.32万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
1979
资助国家：
美国
起止时间：
1979-08-01 至 1992-12-31
项目状态：
已结题

项目摘要

The overall objective of this renewal grant is to analyze the process of liver carcinogenesis in a well defined model of nutritional deficiency and to gain a better understanding of the mechanisms of nutritional modifications of cancer development. Choline deficiency leads to a variety of pathological lesions due to a decrease in phospholipid and acetylcholine synthesis and in the supply of labile methyl groups. Co-carcinogenic effect of a choline deficient (CD) diet on liver cancer induction is primarily mediated through its promoting action, though the debates as to the complete carcinogenicity of the diet per se persist. Several agents which modify the promoting efficacy of a CD diet have been identified, such as the quality of fat, hypolipidemic agents, methapyrilene, antioxidant and phenobarbital. A CD diet induces peroxidative damage of liver microsomal membrane lipids and the extent of lipid peroxidation modified by various agents was positively correlated with the efficacy of tumor promotion with the exception of phenobarbital. We postulate that one of the critical cellular changes relevant to tumor promotion resulting from the diet-induced lipid peroxidation may be functional alterations of the cell membranes. Our initial attempt indicated that there were changes in insulin receptors in CD-hepatocytes and hepatoma cells which may be one manifestation of broader alterations of cell membrane receptors involving cell growth control. We propose to extend our studies in several directions by evaluating i) effects of polyunsaturated fat have a high n-3 fatty acid content (fish oil) on CD promotion, ii) possible significance of the reported CD diet induced lipid peroxidation in nuclear fraction of hepatocytes, iii) the diet induced changes in selected membrane receptors for growth control (insulin, glucagon, insulin like growth factors and EGF) iv) receptor changes by different types of liver tumor promoters and v) sequential changes of growth factor receptors in preneoplastic and neoplastic lesions during CD promotion. These studies will provide critical information regarding possible consequences of the diet-induced membrane lipid peroxidation and its mechanistic significance related to liver tumor promotion.

这项续期拨款的整体目标是分析在一种明确的肝癌发生过程中的模型营养缺乏症和更好地了解癌症发生过程中营养改变的机制。胆碱缺乏会导致多种病理损害与磷脂和乙酰胆碱合成减少有关不稳定的甲基的供应。A的共同致癌作用胆碱缺乏(Cd)饮食对诱发肝癌的作用通过其促进行动进行调解，尽管关于饮食本身的完全致癌性仍然存在。几个改变CD饮食的促进效果的试剂有已经确定，例如脂肪的质量，降血脂药物，甲基吡喃、抗氧化剂和苯巴比妥。镉饮食会导致肝微粒体膜脂过氧化损伤及其机制的研究经不同试剂修饰的脂质过氧化程度与促癌效果呈正相关苯巴比妥除外。我们假设其中一个与肿瘤促进相关的关键细胞变化导致从饮食诱导的脂质过氧化可能起作用细胞膜的改变。我们最初的尝试表明 CD-肝细胞的胰岛素受体发生了变化而肝癌细胞可能是更广泛的一种表现与细胞生长有关的细胞膜受体的变化控制力。我们建议将我们的研究扩展到以下几个方向：评估i)多不饱和脂肪具有高n-3脂肪酸的效果酸含量(鱼油)对镉的促进作用，II)可能的意义已报道的镉饮食可引起细胞核的脂质过氧化肝细胞组分，III)饮食诱导的选定的用于生长控制的膜受体(胰岛素、高血糖素、胰岛素如生长因子和EGF)IV)受体的变化肝肿瘤促进剂的类型和v)顺序变化癌前病变和肿瘤性病变中的生长因子受体在CD推广期间。这些研究将提供关键的关于饮食诱导的可能后果的信息膜脂过氧化及其机制意义与促进肝脏肿瘤有关。