Z24系列化合物一般毒性的比较研究

目的:对具有较强抗肿瘤活性的Z24系列化合物进行一般毒性的比较研究,从中选出毒性较低的候选新药做进一步开发.方法:采用急性毒性上下法和MTT比色法比较5种Z24系列化合物的体内外急性毒性,利用HepG2细胞长期蛋白合成抑制试验评价Z24的长期毒性潜能.结果:Z24系列化合物的急性经口毒性LD50为232.0～＞2 000 mg/kg,SU5416的毒性最低,Z24次之;对CHL细胞的体外细胞毒性IC50为0.019～0.071 mmol/L,Z24的毒性最低.体外染毒6周后Z24对HepG2细胞的24 h半数蛋白合成抑制浓度(PI5024h-6w)明显低于染毒前PI5024h,提示Z24具有潜在的长期毒性.结论:将5种化合物的前期药理学和药效学试验结果与本研究的毒理学结果比较,确定Z24是该系列化合物中最具开发前景的候选新药.

The comparative studies on the general toxicity of Z24 serial chemicals

Objectives:To compare the general toxicity of Z24 serial chemicals which show excellent in vitro antineoplastic activities,and to select a candidate from them for further development.Methods: The acute oral toxicity and the in vitro basic cytotoxicity to CHL cells of five Z24 serial chemicals were determined with the up-and-down procedure and MTT colorimetric assay respectively.The long-term toxicity potential of Z24 was assessed with the 6-week protein inhibition test using HepG2 cells.Results: The acute oral LD50 of five Z24 serial chemicals were in the range of 232.0 to >2000 mg/kg,and their in vitro IC50 to CHL cells were between 0.019 and 0.071 mmol/L,with Z24 showing the lowest toxicity among them.After 6 weeks of in vitro Z24 treatment,the concentration of Z24 with a half protein inhibition to HepG2 cells within 24 hours(PI5024h-6w) was lower than its initial value tested before the treatment(PI5024h),suggesting that Z24 had potential long-term toxicity.Conclusion: Based on the previous pharmacological and efficacy test,and the present comparative studies,Z24 is the most promising candidate in the serial chemicals.