Selective toxicity of nitracrine to hypoxic mammalian cells.
Selective toxicity of nitracrine to hypoxic mammalian cells.
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DOI：
10.1038/bjc.1984.34
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发表时间：
1984-02
影响因子：
8.8
通讯作者：
Probert, J C
中科院分区：
文献类型：
--
作者：
Wilson, W R;Denny, W A;Twigden, S J;Baguley, B C;Probert, J C
实体瘤中的低分化细胞对电离辐射具有抗性，并且可能对许多化疗剂的治疗无效。由于这些原因，鉴定对缺氧细胞具有选择性毒性的药物是癌症化疗的重要目标。硝基咪唑类如米索硝唑表现出这种低氧选择性毒性，但具有非常低的剂量效力。1-硝基吖啶衍生物1-硝基-9-（二甲基氨基丙基氨基）吖啶（硝基吖啶）可逆地结合DNA，但也在体内与DNA形成共价加合物。我们已经发现，在培养的低氧条件下，硝基曲林对中国仓鼠卵巢细胞系AA 8具有选择性毒性，其效力比米索硝唑高约10万倍。在这个系统中，氧的作用不是简单的剂量改变，可能部分是因为在缺氧条件下硝基精氨酸的快速代谢失活。用mini col E1质粒PML-21进行的粘度测定研究证实，硝基曲林通过嵌入与DNA结合，并提供了16度的解旋角（相对于乙锭的26度）。有人提出，缺氧条件下的细胞毒性的硝基曲林是由于还原代谢，形成一个烷基化的物种，但插入的生色团可能会提高对DNA的反应性，因此有助于显着增强效力相对于简单的硝基杂芳族药物。
Hypoxic cells in solid tumours are resistant to ionizing radiation and may be refractory to treatment by many chemotherapeutic agents. For these reasons the identification of drugs with selective toxicity towards hypoxic cells is an important objective in cancer chemotherapy. Nitroimidazoles such as misonidazole demonstrate such hypoxia-selective toxicity but have very low dose potency. The 1-nitroacridine derivative 1-nitro-9-(dimethylaminopropylamino)acridine (nitracrine) binds reversibly to DNA but also forms covalent adducts with DNA in vivo. We have found nitracrine to be selectively toxic to the Chinese hamster ovary cell line AA8 under hypoxic conditions in culture, with a potency approximately 100,000 times higher than that of misonidazole. The effect of oxygen is not a simple dose-modifying one in this system, probably in part because of rapid metabolic inactivation of nitracrine under hypoxic conditions. Viscometric studies with the mini col E1 plasmid PML-21 confirmed that nitracrine binds to DNA by intercalation, and provided an unwinding angle of 16 degrees (relative to 26 degrees for ethidium). It is proposed that the cytotoxicity of nitracrine under hypoxia is due to reductive metabolism to form an alkylating species, but that intercalation of the chromophore may enhance reactivity towards DNA and hence contribute to the marked enhancement of potency with respect to simple nitroheteroaromatic drugs.