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目的:利用斑马鱼胚胎评价抗肿瘤药物去水卫矛醇(DAG)的安全性。方法:以受精后6 h(6 hpf)发育正常的斑马鱼胚胎作为实验对象,分别暴露于A,B两个不同实验组的DAG溶液中,A组:98.00,110.00,125.00,141.00,160.00 mg·L~(-1)的低质量浓度剂量组,B组:661.00,871.00,1 148.00,1 514.00,1 995.00 mg·L~(-1)的高质量浓度剂量组,两组均设空白组,每隔24 h更换一次DAG溶液。观察药物处理至不同时间点时斑马鱼胚胎的发育情况,计算半数致死浓度(LC50),半数致畸效应浓度(EC50),治疗指数(TI)和安全指数(SI)。结果:B组斑马鱼胚胎在48 hpf时心率随着DAG浓度增大而下降,48,72,96 hpf孵化率随着观察时间点不同呈现不同趋势,与空白组比较有统计学差异(P<0.01)。斑马鱼胚胎的畸形率和死亡率均随着给药浓度增大和给药时间的延长而增加(P<0.01)。72 hpf的LC50为1 851.33 mg·L~(-1),EC50为184.50 mg·L~(-1),TI为10.03 mg·L~(-1),SI为1.59 mg·L~(-1);96 hpf的LC50为1 071.96 mg·L~(-1),EC50为74.76 mg·L~(-1),TI为14.34 mg·L~(-1),SI为2.94 mg·L~(-1);6 dpf的LC50为133.12 mg·L~(-1)。结论:DAG的浓度与斑马鱼胚胎发育的毒性存在量效关系;DAG作用时间长短与斑马鱼胚胎发育毒性也存在明显的剂量效应。DAG安全性评价指数相对较高。
Objective: To evaluate the safety of anti-tumor drug dehydrolalcolol (DAG) by using zebrafish embryos. Methods: Normal zebrafish embryos developed 6 h (6 hpf) after fertilization were used as experimental subjects and exposed to DAG solutions of two different experimental groups A and B respectively. Group A: 98.00, 110.00, 125.00, 141.00 and 160.00 mg · The group with low mass concentration of L ~ (-1) and the group with high mass concentration of 661.00, 871.00, 1 148.00, 1 514.00 and 1 995.00 mg · L ~ (-1) , Change the DAG solution every 24 h. To observe the development of zebrafish embryos at different time points after drug treatment, LC50, EC50, TI and SI were calculated. Results: At 48 hpf, the heart rate of the zebrafish embryos in group B decreased with the increasing of DAG concentration. The hatching rates of 48, 72 and 96 hpf showed different trends with different observation time points, which were significantly different from those in the blank group (P < 0.01). The abnormality rate and mortality of zebrafish embryos increased with the increase of drug concentration and administration time (P <0.01). The LC50 of 72 hpf was 1 851.33 mg · L -1, EC50 was 184.50 mg · L -1, TI was 10.03 mg · L -1, SI was 1.59 mg · L -1 ), LC50 of 96 hpf was 1 071.96 mg · L -1, EC50 was 74.76 mg · L -1, TI was 14.34 mg · L -1, SI was 2.94 mg · L -1 -1). The LC50 of 6 dpf was 133.12 mg · L -1. CONCLUSION: The dose-effect relationship between DAG concentration and zebrafish embryo development has the dose-effect relationship. The duration of DAG and zebrafish embryo developmental toxicity also have obvious dose-effect relationship. DAG safety evaluation index is relatively high.