Kai S, Kohmura H, Hiraiwa E, Koizumi S, Ishikawa K, Kawano S, Kuroyanagi K, Hattori N, Chikazawa H, Kondoh H
Preclinical Research Laboratories, Bristol-Myers Squibb K.K., Aichi, Japan.
J Toxicol Sci. 1994 Aug;19 Suppl 1:93-111. doi: 10.2131/jts.19.supplementi_93.
Paclitaxel, an antineoplastic agent, was administered intravenously to pregnant Crj: CD (SD) rats daily at dose levels of 0 (saline and vehicle), 0.1, 0.3 and 1.0 mg/kg from day 17 of gestation to postpartum day 21. Results were as follows: 1. The vehicle-treated group had no effect in any of the parameters that were measured in this study when compared to the saline-treated group. 2. 1.0 mg/kg paclitaxel caused suppression of the body weight gains associated with the decreased food consumption in F0 dams during the lactation period. 3. Thymic, heart and uterine weights were reduced in 1.0 mg/kg F0 dams at completion of the lactation period. In addition, thymic atrophy was observed for 1.0 mg/kg F0 dams macroscopically. 4. Paclitaxel did not alter the delivery status of F0 dams or birth, viability and weaning indices in F1 pups. 5. The days required for presence of hair, incisor eruption and testicular descent were statistically delayed in 1.0 mg/kg F1 rats. 6. The latency time for olfactory orientation was prolonged in 1.0 mg/kg F1 rats on postnatal day 15. Further, the positive response rates for air righting were reduced in 1.0 mg/kg F1 rats from postnatal day 17 to day 20. 7. 1.0 mg/kg paclitaxel caused suppression of the body weight gains in male F1 rats from postnatal week 1 to week 12. Though body weight gains were decreased in 1.0 mg/kg female F1 rats from postnatal week 1 to week 7, there were no significant differences between dosed animals and saline-treated animals regarding the body weight gains and food consumption during the gestation period. 8. Paclitaxel did not affect the learning ability and memory, spontaneous motor activity or emotionality in F1 rats. 9. The reproductive performance in both male and female F1 rats were not affected by paclitaxel. 10. Splenic weights were reduced in 1.0 mg/kg male and female F1 rats at weaning. Furthermore, liver weights were decreased in 1.0 mg/kg male F1 rats after mating. 11. No influence on prenatal development was observed for F2 fetuses even at the highest dose level of paclitaxel. Based on the reproductive and developmental indices, the no toxic-effect dose level of paclitaxel is 1.0 mg/kg/day and 0.3 mg/kg/day for dams (F0) and their offspring (F1), respectively.
将抗肿瘤药物紫杉醇从妊娠第17天至产后第21天，以0（生理盐水和赋形剂）、0.1、0.3和1.0mg/kg的剂量水平每日静脉注射给怀孕的Crj:CD(SD)大鼠。结果如下：1.与生理盐水处理组相比，赋形剂处理组在本研究中测量的任何参数上均无影响。2.1.0mg/kg紫杉醇导致哺乳期F0母鼠体重增加受到抑制，同时食物摄入量减少。3.哺乳期结束时，1.0mg/kg F0母鼠的胸腺、心脏和子宫重量减轻。此外，肉眼观察到1.0mg/kg F0母鼠出现胸腺萎缩。4.紫杉醇未改变F0母鼠的分娩状态或F1幼崽的出生、存活和断奶指数。5.1.0mg/kg F1大鼠出现毛发、门齿萌出和睾丸下降所需的天数在统计学上延迟。6.1.0mg/kg F1大鼠在出生后第15天嗅觉定向的潜伏期延长。此外，1.0mg/kg F1大鼠从出生后第17天至第20天的翻正反射阳性反应率降低。7.1.0mg/kg紫杉醇导致雄性F1大鼠从出生后第1周至第12周体重增加受到抑制。虽然1.0mg/kg雌性F1大鼠从出生后第1周至第7周体重增加减少，但在妊娠期，给药动物与生理盐水处理动物在体重增加和食物摄入量方面没有显著差异。8.紫杉醇不影响F1大鼠的学习能力、记忆、自发运动活动或情绪。9.紫杉醇对雄性和雌性F1大鼠的生殖性能均无影响。10.1.0mg/kg雄性和雌性F1大鼠断奶时脾脏重量减轻。此外，1.0mg/kg雄性F1大鼠交配后肝脏重量减轻。11.即使在紫杉醇最高剂量水平下，也未观察到对F2胎儿产前发育的影响。根据生殖和发育指标，紫杉醇对母鼠（F0）及其后代（F1）的无毒性作用剂量水平分别为1.0mg/kg/天和0.3mg/kg/天。
