LIVER CANCERS BY HYPOLIPIDEMIC PEROXISOME PROLIFERATORS

该提案旨在澄清看似矛盾的 低脂性过氧化物酶增殖物对小鼠肝肿瘤的诱导作用 实验动物。虽然长期服用这些药物会导致 对于肝脏肿瘤的诱发，其短期作用是抑制的。 也不能预防可能的癌前病变的诱发。连 尽管低脂血症过氧化物体的致癌性假说 增殖物可能通过过量产生潜在的 过氧化体持续升高对氧自由基的破坏作用 脂肪酸氧化是有吸引力的，我们的初步研究表明 这些药物(BR931，DEHP)短期给药对大鼠有 不会对肝膜脂质造成过氧化损伤。在这份提案中， 我们将评估细胞大分子的过氧化损伤是否可能 在较长时间服用降血脂药后表现出来 过氧化物体增殖剂和/或给老年动物用药时。 我们将确定这些药物对微粒体和 肝细胞的核膜脂质过氧化和DNA损伤 对衰老大鼠的影响。选定的细胞酶的平衡 负责产生过氧化氢(棕榈酰辅酶A氧化)和 防止过氧化损伤(过氧化氢酶、超氧化物歧化酶、 谷胱甘肽-过氧化物酶和谷胱甘肽等)将被评估为 确定酶活性随时间或年龄的变化。这个 致癌物诱发癌前病变的预防和消退本质 细胞转化为正常肝细胞。最后，将仔细研究这种可能性。 低血脂所致肝肿瘤的前驱病变 过氧化物酶增殖物可能不是普遍接受的酶损伤 病灶改变了。使用各种酶标记物，H3-胸腺嘧啶核苷放射自显影 和抗癌前病变的单抗通过 将对低脂血症性过氧化物酶增殖物进行分析以确定 回归是否代表选择性细胞杀伤或表型 癌前细胞的逆转，我们将分析细胞的变化 与慢性服用这些药物的中间阶段有关 探员们。澄清可能的分离机制(急性和慢性) 这些药物在肝脏上发挥作用将提供 关于控制肿瘤发生和发展的关键信息 一般都是癌症。

The proposal is aimed at clarifying the seemingly contradictory effects of hypolipidemic peroxisome proliferators on the induction of liver tumors in experimental animals. While chronic administration of these agents leads to the induction of liver tumors, their short term effects are inhibitory or preventative to the induction of putative preneoplastic lesions. Even though the hypothesis that carcinogenecity of hypolipidemic peroxisome proliferators may be mediated through excess generation of potentially damaging oxygen radicals as a result of sustained elevation of peroxisomal fatty acid oxidation is attractive, our preliminary study indicates that the short term administration of these agents (BR931, DEHP) to rats does not induce peroxidative damage to liver membrane lipids. In this proposal, we will evaluate whether peroxidative damage to cellular macromolecules may be manifested after relatively long term administration of hypolipidemic peroxisome proliferators and/or when the agents are given to aged animals. We will determine the long term effects of these agents on microsomal and nuclear membrane lipid peroxidation and DNA in hepatocytes damage as well as the effects on aged rats. Balance of selected cellular enzymes responsible for the generation of H2O2 (palmitoyl CoA oxidation) and for protection against peroxidative damage (catalase, superoxide dismutases, glutathione-peroxidases, and glutathione, etc) will be evaluated to determine time or age dependent alterations of the enzyme activities. The nature of prevention and regression of carcinogen-induced preneoplastic cells to normal hepatocytes. Finally, the possibility will be scrutinized that the precursor lesions of liver tumors induced by hypolipidemic peroxisome proliferators may not be the commonly accepted lesions of enzyme altered foci. Using various enzyme markers, H3-thymidine radioautography and monoclonal antibodies against putative preneoplastic foci by hypolipidemic peroxisome proliferators will be analyzed to determine whether regression represents selective cell killing or phenotypic reversion of preneoplastic cells, we will analyze cellular changes associated with intermediate stages of chronic administration of these agents. Clarification of possible separate mechanisms (acute and chronic) with which these agents exert their effects on the liver will provide critical information regarding the control of genesis and progression of cancer in general.