THERAPIES BASED ON ANTIOXIDANT ENZYME MODULATION

基于抗氧化酶调节的疗法

基本信息

批准号：
6616893
负责人：
LARRY OBERLEY
金额：
$ 11.34万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-24 至 2003-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6616893
关键词：
Adenoviridae antineoplastics antioxidants athymic mouse carmustine catalase combination cancer therapy doxorubicin enzyme activity enzyme inhibitors gene therapy neoplasm /cancer neoplasm /cancer chemotherapy neoplasm /cancer photoradiation therapy neoplasm /cancer therapy nonhuman therapy evaluation superoxide dismutase transfection /expression vector tumor necrosis factor alpha

Adenoviridae antineoplastics antioxidants athymic mouse carmustine catalase combination cancer therapy doxorubicin enzyme activity enzyme inhibitors gene therapy neoplasm /cancer neoplasm /cancer chemotherapy neoplasm /cancer photoradiation therapy neoplasm /cancer therapy nonhuman therapy evaluation superoxide dismutase transfection /expression vector tumor necrosis factor alpha

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项目摘要

DESCRIPTION (provided by applicant): During the first four years of the PPG, we have developed a new anticancer combination using adenovirus to deliver the manganese-containing superoxide dismutase (MnSOD) cDNA plus the commonly used anticancer agent BCNU. We have found this to be a very effective antitumor combination that exhibits very little normal cell toxicity when given intratumorally. We believe this protocol works because AdMnSOD raises intracellular peroxide levels and BCNU inhibits peroxide removal. Peroxides are very toxic to cancer cells. In the proposal, we plan to determine if we can obtain even better therapies based on similar principles and to examine further the mechanism of action. Specifically, we will examine the anticancer effects of AdMnSOD given with several compounds besides BCNU. These compounds are all modulators of the glutathione system, which aids in peroxide removal. In addition, we will see if inhibition of the other major peroxide removal system (catalase) will also add to the antitumor effect. We will determine if the copper- and zinc- containing superoxide dismutase (CuZnSOD) is also effective when combined with BCNU. We will ascertain whether the antitumor combinations studied are working as proposed by measuring the levels of various antioxidant and antioxidant proteins modulated. Last, we will determine if superoxide generation via commonly used anticancer agents (ionizing radiation, photodynamic therapy, adriamycin and tumor necrosis factor) or nitric oxide generation will increase the cancer cell killing induced by AdMnSOD plus BCNU.

描述（由申请人提供）：在PPG的前四年中，我们已经使用腺病毒开发了一种新的抗癌组合来提供含锰的超氧化物歧化酶（MNSOD）cDNA以及常用的抗癌剂BCNU。我们发现这是一种非常有效的抗肿瘤给出时表现出很少正常细胞毒性的组合肿瘤内。我们认为该协议有效，因为ADMNSOD会增加细胞内过氧化物水平和BCNU抑制过氧化物的去除。过氧化物对癌细胞非常毒。在提案中，我们计划确定我们是否可以根据类似的原则获得更好的疗法，并检查进一步的作用机理。具体而言，我们将研究ADMNSOD的抗癌作用 BCNU以外的几种化合物。这些化合物都是谷胱甘肽系统，有助于过氧化物去除。此外，我们会看到如果抑制其他主要的过氧化剂去除系统（过氧化氢酶）也将添加到抗肿瘤效果中。我们将确定铜和锌是否是否结合使用，含有超氧化物歧化酶（CuznSOD）也有效 BCNU。我们将确定所研究的抗肿瘤组合是否有效通过测量各种抗氧化剂和抗氧化剂的水平提出蛋白质调节。最后，我们将确定是否通过常用的抗癌药（电离辐射，光动力疗法，阿霉素和肿瘤坏死因子）或一氧化氮的产生将增加 ADMNSOD PLUS BCNU诱导的癌细胞杀伤。