LIVER CANCERS BY HYPOLIPIDEMIC PEROXISOME PROLIFERATORS

该提案旨在澄清 降血脂过氧化物酶体增殖物对诱导肝癌的作用 实验动物 虽然长期服用这些药物会导致 对肝肿瘤的诱导，其短期效应是抑制性的， 或预防推定的肿瘤前病变的诱导。 甚至 尽管低血脂过氧化物酶体的致癌性 增殖物可能通过过度产生潜在的 由于过氧化物酶体的持续升高而破坏氧自由基 脂肪酸氧化是有吸引力的，我们的初步研究表明， 短期给予大鼠这些试剂（BR 931、DEHP） 不引起肝细胞膜脂质过氧化损伤。 在这一提议中， 我们将评估细胞大分子的过氧化损伤是否可能 在相对长期的降血脂治疗后表现出来 过氧化物酶体增殖剂和/或当药剂给予老年动物时。 我们将确定这些药物对微粒体的长期影响， 肝细胞核膜脂质过氧化和DNA损伤 对老年大鼠的影响。 选定细胞酶的平衡 负责产生H2 O2（棕榈酰CoA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）将进行评估， 确定酶活性的时间或年龄依赖性变化。 的 致癌物诱发癌前病变的预防和消退本质 正常肝细胞。 最后，将仔细审查这种可能性 低血脂引起的肝肿瘤的前驱病变 过氧化物酶体增殖物可能不是酶的普遍接受的损伤， 改变焦点 使用各种酶标记物，H3-胸苷放射自显影 和针对推定的癌前病灶的单克隆抗体， 将分析降血脂过氧化物酶体增殖物，以确定 回归是否代表选择性细胞杀伤或表型 肿瘤前细胞的逆转，我们将分析细胞变化 与这些药物长期给药的中间阶段有关 剂. 澄清可能的单独机制（急性和慢性） 这些药物对肝脏发挥作用的方式将提供 关于控制疾病发生和发展的关键信息 癌症一般。

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.