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Effect of addition of superoxide or nitric oxide on the antitumor combination of AdMnSOD plus BCNU.

机译：添加超氧化物或一氧化氮对AdMnSOD和BCNU抗肿瘤组合的影响。

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摘要

It has been reported that MnSOD has a tumor suppressor effect in a wide variety of different cancer cell types and overexpressing MnSOD sensitizes cancer cells to certain anticancer chemotherapy regents, such as BCNU. The purpose of our studies are (1) to explore the mechanism of MnSOD overexpression induced cellular sensitization to BCNU; (2) to determine if increasing the endogenous superoxide production can enhance the antitumor effect of AdMnSOD plus BCNU; (3) to test if nitric oxide application can increase the antitumor effect of the combination of MnSOD overexpression plus BCNU.; BCNU treatment inhibited the glutathione reductase activity but not other major antioxidant enzymes, including MnSOD, CuZnSOD, and catalase, in breast cancer cell lines in a dose and time dependent manner. MnSOD overexpression sensitized cells to the cytotoxicity of BCNU and this sensitization could be reversed by pyruvate. AdMnSOD plus BCNU increased the GSSG percentage in cells and increased the DNA damage.; To test the effect of hydrogen peroxide accumulation on tumor killing, cells were pretreated with AdMnSOD plus BCNU, and then different superoxide-producing modalities (antimycin, TNF-alpha, adriamycin, photofrin(TM)-PDA, and ionizing radiation) were used. Cell viability was measured by the clonogenic assay or trypan blue dye exclusion assay and the production of hydrogen peroxide was detected with the DCFH probe. The results showed that when cells were treated with AdMnSOD plus BCNU and other superoxide radical-producing agents, there were significant increases in the cytotoxicity, the percentage of GSSG, and the prooxidant accumulation. In vivo experiment showed that the combination of AdMnSOD, BCNU, and adriamycin significantly decreased the xenograft volume and prolonged animal tumor-free survival.; To test if nitric oxide mediates the anti-tumor effect of MnSOD, iNOS cDNA was delivered by adenovirus-mediated transduction and different nitric oxide producers (SNP, SIN-1, and DETANONOate) were used. The production of nitric oxide and the cell survival were measured. The results showed that the combination of MnSOD, BCNU and nitric oxide producer significantly increase the cell killing induced by either alone.
机译：据报道，MnSOD在多种不同的癌细胞类型中具有肿瘤抑制作用，并且过表达MnSOD使癌细胞对某些抗癌化学试剂例如BCNU敏感。我们的研究目的是：（1）探讨MnSOD过表达诱导细胞对BCNU致敏的机制； （2）确定增加内源性超氧化物的产生是否可以增强AdMnSOD加BCNU的抗肿瘤作用； （3）测试一氧化氮的施用是否可以增加MnSOD过表达加BCNU的组合的抗肿瘤作用； BCNU处理以剂量和时间依赖性方式抑制乳腺癌细胞系中的谷胱甘肽还原酶活性，但不抑制其他主要抗氧化剂酶，包括MnSOD，CuZnSOD和过氧化氢酶。 MnSOD过表达使细胞对BCNU的细胞毒性致敏，而丙酮酸可以逆转这种致敏作用。 AdMnSOD加BCNU增加了细胞中GSSG的百分比，并增加了DNA损伤。为了测试过氧化氢积累对肿瘤杀死的影响，将细胞用AdMnSOD加BCNU预处理，然后使用不同的超氧化物生成形式​​（抗霉素，TNF-α，阿霉素，photofrinTM-PDA和电离辐射）。通过克隆形成测定或锥虫蓝染料排除测定来测量细胞活力，并且用DCFH探针检测过氧化氢的产生。结果表明，当用AdMnSOD加BCNU和其他超氧化物自由基产生剂处理细胞时，细胞毒性，GSSG百分比和促氧化剂积累显着增加。体内实验表明，AdMnSOD，BCNU和阿霉素的组合显着降低了异种移植物的体积并延长了动物的无瘤生存期。为了测试一氧化氮是否介导MnSOD的抗肿瘤作用，通过腺病毒介导的转导传递了iNOS cDNA，并使用了不同的一氧化氮产生剂（SNP，SIN-1和DETANONOate）。测量一氧化氮的产生和细胞存活。结果表明，MnSOD，BCNU和一氧化氮产生剂的组合显着增加了二者单独诱导的细胞杀伤力。

著录项

  • 作者

    Sun, Wenqing.;

  • 作者单位

    The University of Iowa.;

  • 授予单位 The University of Iowa.;
  • 学科 Health Sciences Oncology.; Health Sciences Radiology.
  • 学位 Ph.D.
  • 年度 2004
  • 页码 120 p.
  • 总页数 120
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 肿瘤学;预防医学、卫生学;
  • 关键词

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