THERAPIES BASED ON ANTIOXIDANT ENZYME MODULATION

描述(由申请人提供)：在PPG的头四年， 我们已经开发了一种新的抗癌药物，使用腺病毒来传递 含锰超氧化物歧化酶(MnSOD)cDNA加常用的 抗癌剂BCNU。我们发现这是一种非常有效的抗肿瘤药物 给药时表现出极小的正常细胞毒性的组合 肿瘤内。我们相信这个协议是有效的，因为AdMnSOD提高了 细胞内过氧化氢水平和BCNU抑制过氧化氢的清除。过氧物 对癌细胞有很强的毒性。在提案中，我们计划确定我们是否 可以基于类似的原理获得更好的治疗方法，并检查 进一步完善作用机制。 具体地说，我们将检查AdMnSOD的抗癌作用 除BCNU外，还有几个化合物。这些化合物都是生物体的调节剂。 谷胱甘肽系统，有助于清除过氧化氢。另外，我们将看到 如果抑制另一个主要的过氧化氢清除系统(过氧化氢酶)也会 增加了抗肿瘤的作用。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药物组合是否有效 通过测量各种抗氧化剂和抗氧化剂的水平提出的 蛋白质被调节。最后，我们将确定超氧化物是否通过 常用抗癌药物(电离辐射、光动力疗法、 阿霉素和肿瘤坏死因子)或一氧化氮的生成将增加 AdMnSOD联合BCNU对肿瘤细胞的杀伤作用。

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.