THERAPIES BASED ON ANTIOXIDANT ENZYME MODULATION

基于抗氧化酶调节的疗法

• 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
• 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

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， 我们开发了一种新的抗癌组合，使用腺病毒来传递 含锰超氧化物歧化酶 (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药物 给予时表现出非常小的正常细胞毒性的组合 瘤内。 我们相信该协议有效，因为 AdMnSOD 提高了 细胞内过氧化物水平和 BCNU 抑制过氧化物去除。过氧化物 对癌细胞有很强的毒性。 在提案中，我们计划确定是否 可以根据类似的原理获得更好的治疗方法并检查 进一步明确作用机制。 具体来说，我们将检查 AdMnSOD 的抗癌作用 除 BCNU 之外的几种化合物。 这些化合物都是调节剂 谷胱甘肽系统，有助于去除过氧化物。 此外，我们还将看到 如果抑制其他主要过氧化物去除系统（过氧化氢酶）也会 增加抗肿瘤作用。 我们将确定铜和锌是否 含有超氧化物歧化酶（CuZnSOD）的药物与 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 蛋白质受到调节。 最后，我们将确定超氧化物是否通过 常用的抗癌药物（电离辐射、光动力疗法、 阿霉素和肿瘤坏死因子）或一氧化氮的生成会增加 AdMnSOD 加 BCNU 诱导的癌细胞杀伤作用。