Adaptation of human tumor cells to tirapazamine under aerobic conditions - Implications of increased antioxidant enzyme activity to mechanism of aerobic cytotoxicity
Adaptation of human tumor cells to tirapazamine under aerobic conditions - Implications of increased antioxidant enzyme activity to mechanism of aerobic cytotoxicity
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DOI：
10.1016/s0006-2952(97)00171-8
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发表时间：
1997-07-15
影响因子：
5.8
通讯作者：
Brown, JM
中科院分区：
文献类型：
--
作者：
Elwell, JH;Siim, BG;Brown, JM
替拉扎明（TPZ，3-氨基-1，2，4-苯并三嗪1，4-二-N-氧化物，SR 4233，WIN 59075）是一种对缺氧细胞具有高选择性毒性的生物还原性抗肿瘤剂。TPZ的选择性缺氧毒性是由于在分子氧存在下，单电子还原产物TPZ自由基快速再氧化，同时产生超氧自由基。在缺氧条件下，TPZ自由基通过引起DNA双链断裂和染色体畸变杀死细胞。然而，有氧细胞毒性的机制仍然是一个有争议的问题。在这项研究中，我们研究了有氧细胞毒性的机制，通过适应人肺腺癌A549细胞的有氧TPZ暴露和表征与耐药性相关的变化。适应的细胞耐有氧TPZ曝光（剂量修改因子高达9.2），虽然缺氧敏感性基本上没有变化。相对于亲本A549细胞系，适应持续有氧TPZ暴露导致锰超氧化物歧化酶水平升高（高达9.4倍），谷胱甘肽还原酶中度升高（高达2.1倍），醌氧化还原酶（DT黄递酶）活性和NADPH细胞色素P450还原酶活性均丧失。有基本上没有变化的活性的细胞质形式的超氧化物歧化酶（CuZnSOD），过氧化氢酶，或谷胱甘肽过氧化物酶。抗氧化酶在耐药细胞系（特别是MnSOD）的活性增加，强烈表明，活性氧物种，在很大程度上，负责TPZ在有氧条件下的毒性，是一致的有氧和缺氧的药物细胞毒性产生的不同机制。(C)1997年爱思唯尔科学公司
Tirapazamine (TPZ, 3-amino-1,2,4-benzotriazine 1,4-di-N-oxide, SR 4233, WIN 59075) is a bioreductive antitumor agent with a high selective toxicity for hypoxic cells. The selective hypoxic toxicity of TPZ results from the rapid reoxidation of the one-electron reduction product, the TPZ radical, in the presence of molecular oxygen with the concomitant production of superoxide radical. Under hypoxia the TPZ radical kills cells by causing DNA double-strand breaks and chromosome aberrations. However, the mechanism of aerobic cytotoxicity is still a matter of debate. In this study, we investigated the mechanism of aerobic cytotoxicity by adapting human lung adenocarcinoma A549 cells to aerobic TPZ exposure and characterizing the changes associated with drug resistance. The adapted cells were resistant to aerobic TPZ exposures (with dose-modifying factors of up to 9.2), although hypoxic sensitivity was largely unchanged. Relative to the parental A549 cell line, adaptation to continuous aerobic TPZ exposure resulted in increased levels of manganese superoxide dismutase (up to 9.4-fold), moderate increases in glutathione reductase (up to 2.1-fold), and loss of both quinone oxidoreductase (DT diaphorase) activity and NADPH cytochrome P450 reductase activity. There was essentially no change in the activity of the cytoplasmic form of superoxide dismutase (CuZnSOD), catalase, or glutathione peroxidase. The increased activity of antioxidant enzymes in the resistant cell lines (in particular MnSOD) strongly suggests that reactive oxygen species are, in large part, responsible for the toxicity of TPZ under aerobic conditions, and is consistent with aerobic and hypoxic drug cytotoxicity resulting from different mechanisms. (C) 1997 Elsevier Science Inc.