康普瑞汀磷酸钠对大鼠胚胎发育毒性的研究

Embryotoxicity study of combretastatin A-4 disodium phosphate(CA4P) in rats

目的：探讨抗肿瘤药物康普瑞汀磷酸钠（combretastatin A-4 disodium phosphate，CA4P）对SD孕鼠胚胎发育的毒性作用。方法：80只孕鼠随机分为低剂量（0．15mg／kg）组、中剂量（0．50mg／kg）组和高剂量（1．50mg／kg）组及对照组（生理盐水），每组20只，给药容积均为10mL／kg。于妊娠第以15日尾静脉注射给药，每日1次。妊娠第20日解剖孕鼠，检查母体妊娠与胎鼠畸形情况。结果：与对照组比较，高剂量组的着床率、胚胎吸收率均有显著升高，活胎率降低，差异均有统计学意义（P〈0．05）；妊娠后期高剂量组孕鼠体质量增长显著低于对照组，差异有统计学意义（P〈0．05）；中、高剂量组的胎盘质量、活胎体质量、活胎顶臀长以及尾椎数、掌骨数、枕骨数、胸骨数均显著减少（P〈0．05）；各剂量组未见胎鼠外观及内脏畸形。结论：本实验条件下，CA4P对亲代孕鼠未观察到不良反应的剂量水平（NOAEL）为0．50mg／kg，对胚胎、胎仔发育的NOAEL为0．15mg/kg，对胎仔致畸作用的NOAEL为1．50mg/kg。

Objective： To investigate the embryotoxicity of combretastatin A-4 disodium phosphate （CA4P） in pregnancy SD rats. Methods： Eighty SD rats were randomly divided into 4 groups （n=20 for each group）. Three experimental dosages （0.15 mg/kg, 0.50 mg/kg, 1.50 mg/kg） were chosen, SD rats were injected intravenously with experimental agent or normal saline as control. The injection was conducted from the 6th to 15th day of gestation, once a day. Pregnancy rats were sacrificed on the 20th day of gestation and pregnancy results and embryonic malformation were examined. Results： There were significant differences in the rate of implantation, living and absorbed fetus in 1.50 mg/kg dosage group compared with negative control （P〈0.05）, moreover, the weight gain of the pregnancy rats slowed down in the late gestation stage, which indicated maternal toxicity. Under both 0.50 mg/kg and 1.50 mg/kg dosages group, there were significant differences in placenta weight, living fetus weight body length and number of caudal vertebra, metacarpal bone, occipital bone and breast bone in comparison with control group. All dosage groups did not induce any embrynic teratogenic effect on the appearance or organs. Conclusion： Under these experimental conditions, the no observed adverse effect level （NOAEL） of CA4P on pregnancy rats and embryonic development were 0.50 mg/kg and 0.15 mg/kg, respectively, while the NOAEL on teratogenicity effect was 1.50 mg/kg.