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目的 :检验和评价喹喔啉双氮氧化物衍生物QN 2 0 13的选择性乏氧细胞毒性和放射增敏作用。方法 :体外细胞毒性、放射增敏作用及体内抗肿瘤活性 ,分别用集落形成法和肿瘤生长延迟法检验。细胞周期的变化、DNA损伤和损伤DNA的修复分别以流式细胞术和“彗星”分析法测定。结果 :QN 2 0 13对乏氧和富氧HeLa S3细胞的等毒性浓度ICN250 和ICair50 分别是 0 .0 8和 1.7mmol·L-1,乏氧细胞毒性比率 (hypoxiccytotoxicityratio ,HCR)为 2 1。这说明QN 2 0 13具有一定的乏氧细胞毒性 ,但弱于代表性生物还原药SR 42 33。在 1mmol·L-1以下时 ,QN 2 0 13的体外放射增敏作用比MISO(misonidazole)弱 ,但随药物浓度增加近似按指数增大 ,而荷瘤小鼠腹腔给药则体内增敏作用与施药剂量无明显依赖关系。在细胞和分子水平上 ,QN 2 0 13诱发乏氧HeLa S3细胞G2 M期阻断 ,引起DNA双链断裂 ,且抑制辐射DNA损伤的修复。结论 :QN 2 0 13是一中度活性的乏氧选择性细胞毒剂 ,体内外实验表明具有一定的放射增敏作用 ,明显增强辐射抗肿瘤能力。其作用机制可能是通过直接损伤DNA和抑制DNA修复。这些结果提示虽QN 2 0 13本身可能不是理想的生物还原药 ,但喹喔啉氮氧化物系列不失为探索新抗癌药应重视的领域之一。
Objective : To test and evaluate the selective hypoxia cytotoxicity and radiosensitization of quinoxaline diazonium oxide derivative QN 2 0 13 . METHODS: In vitro cytotoxicity, radiosensitization and antitumor activity in vivo were examined by colony formation assay and tumor growth delay assay, respectively. Changes in cell cycle, DNA damage, and repair of damaged DNA were measured by flow cytometry and “comet assay.” RESULTS: The isotoxic concentrations ICN250 and ICair50 of QN 2 0 13 to hypoxic and oxygen-rich HeLa S3 cells were 0.8 and 1.7 mmol·L-1, respectively, and the hypoxic cytotoxicity ratio (HCR) was 21. This indicates that QN 2 0 13 has some hypoxic cytotoxicity but is weaker than the representative bioreductive drug SR 42 33 . At 1 mmol·L-1 or less, the radiosensitization of QN 2 0 13 was weaker than that of MISO (misonidazole), but it increased exponentially with the increase of drug concentration, whereas the sensitization effect of QN 2 0 13 was increased in vivo in tumor-bearing mice. There is no obvious dependence on the dose. At the cellular and molecular level, QN 2 0 13 induces G2 M phase arrest in hypoxic HeLa S3 cells, causing DNA double-strand breaks and inhibiting repair of radiation DNA damage. Conclusion : QN 2 0 13 is a moderately active hypoxic selective cytotoxic agent. In vitro and in vivo experiments show that it has a certain radiosensitization effect, and it obviously enhances the ability of radiation and anti-tumor. Its mechanism of action may be through direct damage to DNA and inhibition of DNA repair. These results suggest that although QN 2 0 13 itself may not be an ideal bioreductive drug, the quinoxaline nitrogen oxide series may be one of the areas that should be considered in exploring new anticancer drugs.