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以放射自显影的方法研究了三尖杉酯碱对小鼠L-1210白血病细胞的杀伤动力学。三尖杉酯碱20微克/只腹腔注入后3小时,部分腹水细胞出现明显的核损伤,如核碎裂,而胞质的损伤则不明显。以~3H-TdR脉冲标记后0.5小时腹腔注入三尖杉酯碱20微克/只,损伤的标记细胞在给药后5小时为26.1%,损伤的非标记细胞占11.9%,标记指数也随给药而逐时下降,到24小时由对照的28.9%下降到4.6%。给药后3～9小时有丝分裂指数明显下降。以~3H-TdR进行脉冲标记后,用秋水仙酰胺阻断,再给三尖杉酯碱30微克/只,观察标记有丝分裂指数的变化,发现药物强烈抑制S期细胞进入M期。药物杀伤结合秋水仙酰胺抑制实验证明,给药时正处于M期的细胞仍可继续完成分裂,而G_3期细胞进入M期明显受到抑制。连续16小时腹腔注射5微居里/只后,不标记的G_0期细胞占52.3%,此时注射三尖杉酯碱后5小时G_0期细胞的损伤达19.7%。体内、体外试验发现三尖杉酯碱对~3H-TdR、~3H-L-门冬酰胺的参入有明显抑制,在给药后0.5小时即下降至最低点,并持续12～48小时才恢复正常。药物对~3H-TdR参入的抑制与细胞的平均标记颗粒数的减少存在平行关系。根据以上结果认为三尖杉酯碱系属细胞周期非特异性药物,但对S期细胞杀伤较明显。
The cytotoxicity of harringtonine on mouse L-1210 leukemia cells was studied by autoradiography. In the case of harringtonine 20 μg / 3 hours after intraperitoneal injection, some ascites cells showed obvious nuclear damage, such as nuclear fragmentation, whereas cytoplasmic damage was not obvious. After the pulsed ~3H-TdR pulse was injected into the peritoneal cavity, 20 μg of homoharringtonine was injected for 0.5 hour. The number of labelled cells damaged was 26.1% at 5 hours after administration, 11.9% of non-labeled cells were damaged, and the labeling index was also given. The drug dropped from time to time, and dropped from 28.9% of the control to 4.6% within 24 hours. The mitotic index decreased significantly at 3 to 9 hours after administration. After pulsed labeling with ~3H-TdR, it was blocked with colchicine, and 30 g/harringtonine was only given. Changes in labeled mitotic index were observed, and it was found that the drug strongly inhibited S phase cells from entering the M phase. Drug killing combined with colchicine inhibition experiments demonstrated that cells that are in M phase when administered can still continue to divide, while G3 phase cells are significantly inhibited from entering M phase. After a continuous intraperitoneal injection of 5 microcuries per mouse for 16 hours, 50% of the unlabeled cells were in the G 0 phase. At this time, the cytotoxicity of the G 0 cells was 19.7% at 5 hours after the injection of the harringtonine. In vivo and in vitro tests showed that harringtonine significantly inhibited the incorporation of ~3H-TdR and ~3H-L-asparagine, which decreased to the lowest point 0.5 hours after administration and continued for 12 to 48 hours. normal. There was a parallel relationship between the inhibition of ~3H-TdR incorporation by the drug and the decrease in the average number of labeled particles in the cells. Based on the above results, it is considered that harringtonine is a non-specific drug in cell cycle, but it is more effective in killing S-phase cells.