Biaglow J E, Varnes M E, Roizen-Towle L, Clark E P, Epp E R, Astor M B, Hall E J
Biochem Pharmacol. 1986 Jan 1;35(1):77-90. doi: 10.1016/0006-2952(86)90561-7.
Misonidazole is a metabolically active drug. Its addition to cells causes an immediate alteration in cellular electron transfer pathways. Under aerobic conditions the metabolic alterations can result in futile cycling with electron transfer to oxygen and production of peroxide. Thiol levels are extremely important in protecting the cell against the peroxide formation and potentially hazardous conditions for hydroxyl radical production. Nevertheless such electron shunting out of cellular metabolism will result in alterations in pentose cycle, glycolysis and cellular capacity to reduce metabolites to essential intermediates needed in DNA metabolism (i.e. deoxyribonucleotides). Glutathione must be depleted to very low levels before toxic effects of misonidazole and other nitro compounds are manifested in cell death via peroxidative damage. Under hypoxic conditions misonidazole also diverts the pentose cycle via its own reduction; however, unlike the aerobic conditions, there are a number of reductive intermediates produced that react with non-protein thiols such as GSH as well as protein thiols. The reaction with protein thiols results in the inhibition of glycolysis and other as yet undetermined enzyme systems. The consequences of the hypoxic pretreatment of cells with nitro compounds are increased vulnerability to radiation and chemotherapeutic drugs such as L-PAM, cis-platinum and bleomycin. The role that altered enzyme activity has in the cellular response to misonidazole and chemotherapeutic agents remains to be determined. It is also clear that the GSH depleted state not only makes cells more vulnerable to oxidative stress but also to hypoxic intermediates produced by the reduction of misonidazole beyond the one electron stage. The relevancy of the present work to the proposed use of thiol depletion in vivo to enhance the radiation or chemotherapeutic response of tumor tissue lies with the following considerations. Apparently, spontaneous peroxidative damage to normal tissue such as liver can occur with GSH depletion to 10-20% of control and with other normal tissue when GSH reaches 50% of control. This situation can obviously become more critical if peroxide producing drugs are administered. The only advantage to such combined drug treatments would lie in the possibility that tumors vary in their catalase and peroxidase activity and consequently may be more vulnerable to oxidative stress (cf. review by Meister. Our tumor model, the A549 human lung carcinoma cell in vitro, appears to be an exception because it has catalase, peroxidase and a high content of GSH.(ABSTRACT TRUNCATED AT 400 WORDS)
米索硝唑是一种具有代谢活性的药物。将其添加到细胞中会立即改变细胞的电子传递途径。在有氧条件下，代谢改变会导致电子传递给氧并产生过氧化物的无效循环。硫醇水平对于保护细胞免受过氧化物形成以及潜在的羟基自由基产生的危险条件极为重要。然而，这种细胞代谢中的电子分流会导致戊糖循环、糖酵解以及细胞将代谢物还原为DNA代谢所需的必需中间体（即脱氧核糖核苷酸）的能力发生改变。在米索硝唑和其他硝基化合物的毒性作用通过过氧化损伤导致细胞死亡之前，谷胱甘肽必须被消耗到非常低的水平。在缺氧条件下，米索硝唑也会通过自身的还原作用使戊糖循环转向；然而，与有氧条件不同的是，会产生许多还原中间体，它们会与非蛋白质硫醇如谷胱甘肽以及蛋白质硫醇发生反应。与蛋白质硫醇的反应会导致糖酵解和其他尚未确定的酶系统受到抑制。用硝基化合物对细胞进行缺氧预处理的后果是增加了对辐射和化疗药物如左旋苯丙氨酸氮芥、顺铂和博来霉素的敏感性。酶活性改变在细胞对米索硝唑和化疗药物反应中的作用仍有待确定。同样清楚的是，谷胱甘肽耗尽状态不仅使细胞更容易受到氧化应激的影响，而且更容易受到米索硝唑单电子还原阶段之后产生的缺氧中间体的影响。本研究与体内使用硫醇耗竭来增强肿瘤组织的辐射或化疗反应的相关性基于以下考虑。显然，当谷胱甘肽消耗到对照水平的10 - 20%时，正常组织如肝脏可能会发生自发的过氧化损伤，而当谷胱甘肽达到对照水平的50%时，其他正常组织也会如此。如果给予产生过氧化物的药物，这种情况显然会变得更加严重。这种联合药物治疗的唯一优势可能在于肿瘤的过氧化氢酶和过氧化物酶活性可能不同，因此可能更容易受到氧化应激的影响（参见Meister的综述）。我们的肿瘤模型，即体外培养的A549人肺癌细胞，似乎是个例外，因为它具有过氧化氢酶、过氧化物酶且谷胱甘肽含量很高。（摘要截选至400字）
