THERAPIES BASED ON ANTIOXIDANT ENZYME MODULATION

描述（由申请人提供）：在PPG的前四年， 我们已经开发出一种新的抗癌组合， 含锰超氧化物歧化酶（MnSOD）cDNA加上常用的 抗癌剂BCNU。 我们发现这是一种非常有效的抗肿瘤药物 当给药时， 肿瘤内。 我们相信这个方案是有效的，因为AdMnSOD提高了 细胞内过氧化物水平和BCNU抑制过氧化物清除。过氧化物 对癌细胞有很强的毒性 在提案中，我们计划确定我们是否 可以根据类似的原理获得更好的治疗方法， 进一步的行动机制。 具体地说，我们将研究AdMnSOD与 除了BCNU还有几种化合物 这些化合物都是 谷胱甘肽系统，这有助于清除过氧化物。 此外，我们将看到 如果其它主要过氧化物去除系统（过氧化氢酶）的抑制也将 增加抗肿瘤效果。 我们将确定铜和锌- 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 如通过测量各种抗氧化剂和抗氧化剂的水平所提出的， 调节蛋白质。 最后，我们将确定是否通过超氧化物生成 通常使用的抗癌剂（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联合BCNU诱导的癌细胞杀伤作用。

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.