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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。
OBJECTIVE: To compare the general toxicity of Z24 series compounds with strong anti-tumor activity and select the candidate new drugs with lower toxicity for further development. Methods: The acute toxicity in vitro and in vivo of five Z24 compounds were compared using acute toxicity assay and MTT assay. The long-term toxicity of HepG2 cells was evaluated by long-term inhibition of protein synthesis. Results: The acute oral toxicity (LD50) of Z24 series compounds was 232.0-2000 mg / kg, the toxicity of SU5416 was the lowest, followed by Z24. The cytotoxicity of CH24 cells in vitro was 0.019-0.071 mmol / L and the toxicity of Z24 was the lowest . After 24 weeks of in vitro exposure, the inhibitory concentration of half-life of Z24 on HepG2 cells (PI5024h-6w) was significantly lower than that of PI5024h before exposure, suggesting potential long-term toxicity of Z24. Conclusion: The preliminary pharmacological and pharmacodynamic test results of five compounds were compared with the toxicological results of this study, and Z24 was identified as the most promising candidate drug in this series of compounds.