首页 | 本学科首页   官方微博 | 高级检索  
检索        

喹喔啉双氮氧化物衍生物QN-2013的乏氧细胞毒性和放射增敏作用
引用本文:孙小平,李五岭,仉文升,沈恂,赵慧云,吴艳芬,沈磊,汤丽霞,王军.喹喔啉双氮氧化物衍生物QN-2013的乏氧细胞毒性和放射增敏作用[J].北京大学学报(医学版),2001,33(2):140-143.
作者姓名:孙小平  李五岭  仉文升  沈恂  赵慧云  吴艳芬  沈磊  汤丽霞  王军
作者单位:^A北京大学基础医学院放射医学基础教研室,北京 100083^B北京大学^C1447^D1%^A中国科学院生物物理研究所^BBiophysics Institute of Academia Sinica^C881664^D2%^A中国医学科学院肿瘤研究所^BInstitute of Research on Tumor, Chinese Academy of Medical Science^C892022^D3
基金项目:国家自然科学基金;39270235;
摘    要:目的:检验和评价喹喔啉双氮氧化物衍生物QN-2013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-2013对乏氧和富氧HeLa-S3细胞的等毒性浓度ICN250和ICair50分别是0.08和1.7 mmol*L-1,乏氧细胞毒性比率(hypoxic cytotoxicity ratio, HCR)为21。这说明QN-2013具有一定的乏氧细胞毒性,但弱于代表性生物还原药SR-4233。在1 mmol*L-1以下时,QN-2013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-2013诱发乏氧HeLa-S3细胞G2M期阻断,引起DNA双链断裂,且抑制辐射DNA损伤的修复。结论:QN-2013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-2013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。

关 键 词:细胞毒素类/药理学  细胞低氧/药物作用  放射增敏剂/药理学  喹喔啉双氮氧化物  抗肿瘤药/药理学  
文章编号:1000-1530(2001)02-0140-04

Hypoxia-selective cytotoxicity and radiosensitization of quinoxaline 1,4-di-N-oxide derivative, QN-2013
SUN Xiao-ping,LI Wu-Ling,ZHANG Wen-Sheng,SHEN Xun,ZHAO Hui-Yun,WU Yan-Fen,SHEN Lei,TANG Li-xia,WANG Jun.Hypoxia-selective cytotoxicity and radiosensitization of quinoxaline 1,4-di-N-oxide derivative, QN-2013[J].Journal of Peking University:Health Sciences,2001,33(2):140-143.
Authors:SUN Xiao-ping  LI Wu-Ling  ZHANG Wen-Sheng  SHEN Xun  ZHAO Hui-Yun  WU Yan-Fen  SHEN Lei  TANG Li-xia  WANG Jun
Institution:SUN Xiao Ping 1,LI Wu Ling 1,ZHANG Wen Sheng 1,SHEN Xun 2,ZHAO Hui Yun 1,WU Yan Fen 1,SHEN Lei 1,TANG Li Xia 2,WANG Jun 3
Abstract:Objective: To determine the potency of QN-2013, a derivative of quinoxaline 1,4-N-oxide, as a hypoxia-selective cytotoxin or a radiosensitizer. Methods: In vitro cytotoxicity and radiosensitization, as well as in vivo antitumor activity were determined by colony formation and tumor growth delay respectively. The changes in the cell cycle, DNA damage and repair of damaged DNA were assayed by FCM and “comet” assay, separately. Results: ICN250 and ICair50 of QN-2013 for HeLa-S3 cells were 0.08 and 1.7 mmol*L-1 respectively, namely, HCR=21. This suggested that QN-2013 was a fairly hypoxic cytotoxin, but inferior to SR-4233. QN-2013 had an evident radiosensitization either in vitro or in vivo. It was noted, however, that the value of in vitro SERs increased exponentially with increasing concentration of the drug, but the in situ antitumor activity seemed to be independent of doses of the drug. The systemic toxicity of QN-2013 was superior to an LD50 of 265 mg*kg-1 compared with 80 mg*kg-1 for SR-4233. In hypoxic condition QN-2013 induced S retension effect and G2M block in HeLa-S3 cells, caused DNA double strand break, and inhibited the repair of radiation-induced DNA damages. All of these reactivenesses might be involved in the action mechanism of QN-2013. Conclusion: QN-2013 is a fair hypoxia-selective cytotoxin, and has shown improved antitumor activity in vivo in combination with radiation. In general, These results suggest that the series of quinoxaline di-N-oxide derivatives hold out bright prospect for the development of novel bioreductive antitumor drugs.
Keywords:Cytotoxins/pharmacol  Cell hypoxia/drug eff  Radiation  sensitizing agents/pharmacol  Quinoxaline di  N  oxide  Antineoplastic agents/pharmacol
本文献已被 CNKI 万方数据 等数据库收录!
点击此处可从《北京大学学报(医学版)》浏览原始摘要信息
点击此处可从《北京大学学报(医学版)》下载免费的PDF全文
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号