CAJ | 학술논문

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。
목적：검험화평개규악람쌍담양화물연생물QN-2013적선택성핍양세포독성화방사증민작용。방법：체외세포독성、방사증민작용급체내항종류활성，분별용집락형성법화종류생장연지법검험。세포주기적변화、DNA손상화손상DNA적수복분별이류식세포술화“혜성”분석법측정。결과：QN-2013대핍양화부양HeLa-S3세포적등독성농도ICN250화ICair50분별시0.08화1.7 mmol*L－1，핍양세포독성비솔(hypoxic cytotoxicity ratio, HCR)위21。저설명QN-2013구유일정적핍양세포독성，단약우대표성생물환원약SR-4233。재1 mmol*L－1이하시，QN-2013적체외방사증민작용비MISO(misonidazole)약，단수약물농도증가근사안지수증대，이하류소서복강급약칙체내증민작용여시약제량무명현의뢰관계。재세포화분자수평상，QN-2013유발핍양HeLa-S3세포G2M기조단，인기DNA쌍련단렬，차억제복사DNA손상적수복。결론:QN-2013시일중도활성적핍양선택성세포독제，체내외실험표명구유일정적방사증민작용，명현증강복사항종류능력。기작용궤제가능시통과직접손상DNA화억제DNA수복。저사결과제시수QN-2013본신가능불시이상적생물환원약，단규악람담양화물계렬불실위탐색신항암약응중시적영역지일。
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.