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LIVER CANCERS BY HYPOLIPIDEMIC PEROXISOME PROLIFERATORS

低血脂过氧化物酶体增殖剂引起的肝癌

基本信息

批准号：
3179509
负责人：
HISASHI SHINOZUKA
金额：
$ 10.87万
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：
1985
资助国家：
美国
起止时间：
1985-07-01 至 1988-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3179509
关键词：
autoradiography cellular oncology chemical carcinogen chemical carcinogenesis histology liver neoplasms peroxisome radiotracer

项目摘要

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 preventive 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.

该提案旨在澄清看似矛盾的影响降血脂过氧化物酶体增殖物对肝癌诱导作用实验动物。虽然长期服用这些药物会导致对于诱发肝脏肿瘤，其短期效果是抑制性的或预防假定的癌前病变的诱发。甚至尽管低脂血症过氧化物酶体的致癌性假设增殖剂可能是通过潜在的过量产生来介导的由于过氧化物酶体持续升高而破坏氧自由基脂肪酸氧化很有吸引力，我们的初步研究表明短期给予大鼠这些药物（BR931、DEHP）不会不引起肝膜脂质过氧化损伤。在这个提案中，我们将评估细胞大分子的过氧化损伤是否可能长期服用降血脂药后才会显现过氧化物酶体增殖剂和/或将药物给予老年动物时。我们将确定这些药物对微粒体和核膜脂质过氧化和肝细胞DNA损伤如对老年大鼠的影响。所选细胞酶的平衡负责生成 H2O2（棕榈酰 CoA 氧化）并负责防止过氧化损伤（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）将被评估确定酶活性的时间或年龄依赖性变化。这预防和消退致癌物诱发的癌前病变的性质细胞转化为正常肝细胞。最后，将审查可能性低血脂诱发肝肿瘤的前驱病变过氧化物酶体增殖物可能不是普遍接受的酶损伤改变焦点。使用各种酶标记物，H3-胸苷放射自显影和针对假定的肿瘤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长期服用这些药物的中间阶段有关代理。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将提供有关控制发生和进展的关键信息一般癌症。