持续化疗灌注状态下细胞周期非特异性药物与细胞间作用的特性

Action characteristics of the cell cycle nonspecific agents in cell lines in the state of continuous transartery chemotherapy infusion

目的:检测动脉留管持续化疗灌注的药物环境下,不同浓度梯度的高浓度细胞周期非特异性药物(cellcycle nonspecific agents,CCNSA)持续作用不同时间对肝癌细胞系HepG-2及肝细胞系7702的作用,并探索动脉化疗灌注中化疗药有无浓度-时间依赖现象及二者之间的相互联系。方法:根据介入治疗中局部组织能够达到的实际浓度,将4种临床常用的细胞周期非特异性化疗药(表柔比星、草酸铂、顺铂、福莫司汀)分别按照质量浓度比20∶10∶5∶2.5∶1的比例制成5种质量浓度溶液(4种药物的最大质量浓度分别为8 mg/L、20 mg/L、20 mg/L、8 mg/L),每种质量浓度分别与两种细胞系作用1 h、2 h、4 h、6 h、8 h,采用MTT法分别检测25种组合下,化疗药对体外培养的HepG-2及7702细胞系的抑制率。结果:各种药物不同作用浓度及时间对HepG-2肝癌细胞系和7702肝细胞系有不同的抑制率,表柔比星和草酸铂的5种质量浓度间差别不大,其抑制率主要与持续时间相关,随着作用时间延长而逐渐增加;低浓度顺铂的抑制率随着时间的延长缓慢增加,而高浓度顺铂的抑制率则随着时间的延长较快增加;福莫司汀的抑制率与浓度之间缺乏明确关系,但是随着时间的延长缓慢增加。结论:每一种CCNSA化疗药有其适合的作用浓度及持续时间;浓度因素与时间因素均对抑制率有明显影响,但是时间因素影响更大;动脉化疗灌注拥有足够的药物浓度及给药时间,应该选择最低有效浓度和较长的作用时间,这样可以减少用药总量,增加对肿瘤细胞的杀伤,实现介入治疗给药剂量、给药时间精确化。

Objective ： To detect the acting pattern of different high concentrations of cell cycle nonspe- cific agents （CCNSA）, epirubicin, oxaliplatin, cisplatin and fotemustine, acting with HepG-2 and 7702 cell lines respectively for different times; and to explore whether there are concentration and time dependent phenomena for each agent and relations between these two factors. Methods： MTF assays were used to detect inhibition rates of different combinations of concentrations and times in all the agents. Five concentrations were chosen for each agent within the range of clinical practice in interventional thera- py by the ratios of 20： 10：5 ： 2.5 ： 1, the highest concentrations of epirubiein, oxaliplatin, cisplatin and fotemustine was 8 rag/L, 20 mg/L, 20 mg/L and 8 mg/L respectively, and each concentration acted with HepG-2 and 7702 cell lines at 5 different time points which lasted for 1 h, 2 h, 4 h, 6 h, and 8 h, respectively. Results： Different combinations of concentrations and time points had different inhibition rates for HepG-2 and 7702 cell lines. For epirubicin and oxaliplatin, the inhibition rates of 5 concentra- tions had little difference, which mainly depended on time and increased with the increase of lasting time ; cisplatin show with the increase of ed different characteristics： at low concentrations, the inhibition rate increased slowly lasting time, but with the increase of concentration, the inhibition rate increased ob- viously with the increase of lasting time. The inhibition rate of fotemustine lacked obvious connection with the concentrations, but increased with the time at any cencentration. Conclusion： Different CCNSA have their own suitable concentration and time factors, both factors have obvious influence on the inhibitionrate, and the time factor seems more important. Since transartery infusion can provide enough or even over-doseconcentrations, the minimum effective concentration and enough time should be chosen, which could increase the killing of tumor cells, and at the same time decrease the total dose, thus realizing pre- cise artery chemotherapy.