REPRODUCTIVE AND DEVELOPMENTAL TOXICITY STUDIES OF PACLITAXEL (III) : Intravenous administration to rats during the perinatal and lactation periods

Abstract

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.

Epithelial ovarian cancer in pregnancy: a review of the literature

“…Paclitaxel administration in rats during early pregnancy can cause craniofacial malformations, diaphragmatic hernias, and kidney and cardiovascular system defects 70 . In advanced pregnancy, paclitaxel did not affect body weight, learning ability, and memory or spontaneous motor activity 71 …”

Adnexal Masses in Pregnancy

“…High doses of paclitaxel (10 mg/kg/day) applied during early pregnancy (day 8 of gestation) were associated with reduced litter size, reduction of fetal weight, malformations including craniofacial malformations, diafragmatic hernias, and defects of the kidneys, the cardiovascular system, and the tail [38]. In contrast, exposure to lower dosages of paclitaxel (1.0 mg/kg/day) prior to mating, during mating, in early and in advanced pregnancy revealed no significant influence on reproductive outcome and subsequent locomotor-, or neuro-development [39][40][41]. Similar results were observed in pregnant rats treated with carboplatin.…”

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“…The obtained results were consistent with those recorded by 9 who found that, cefeperazone depressed the uterine motility in two of six experiments while during pregnancy, they found that cefoperazone might not affected or depressed and/or stimulated the uterine motility. In other observation, cefepime had no effect on the delivery status of the offspring rats 16 , and 17 who found that, the spontaneous movement and tone of isolated uterus were not affected following cefbuperazone application.…”