Collaborative work on evaluation of ovarian toxicity. 6) Two- or four-week repeated-dose studies and fertility study of cisplatin in female rats.
The main aim of the present study is to determine the optimal administration period of cisplatin with regards to its toxic effects on ovarian morphology in the repeated-dose toxicity study. Cisplatin was administered to female SD rats intraperitoneally once daily at dose levels of 0.25, 0.5, 1.0 and 2.0 mg/kg for 2 weeks, or at dose levels of 0.125, 0.25 and 0.5 mg/kg for 4 weeks in the repeated-dose toxicity study. In the female fertility study, 0.25, 0.5 and 1.0 mg/kg of cisplatin were administered in the same manner from 14 days prior to mating to Day 7 of gestation. In the repeated-dose toxicity study, a decrease in large follicle, an increase in atresia of medium and large follicles, and/or a decrease in currently formed corpus luteum were observed in animals receiving 1.0 and 2.0 mg/kg for 2 weeks, and decreases in small and/or large follicles and an increase in atresia of large follicle were observed in animals receiving 0.25 and 0.5 mg/kg for 4 weeks on the histopathological examination of the ovaries. In the female fertility study, the copulation and fertility indices in the animals receiving 1.0 mg/kg tended to be lower than those in the control animals. In conclusion, histopathological changes in the ovary that were attributable to cisplatin dosing were detected by detailed observation of the ovary in the 2-week study; and therefore, a 2-week administration period is sufficient to evaluate the ovarian toxicity of cisplatin.
Nozaki
Yusuke
Y
Drug Safety Research Department, Toyama Chemical Co., Ltd., Shimookui, Toyama, Japan. yuusuke_nozaki@toyama-chemical.co.jp
Furubo
Eiko
E
Matsuno
Takayuki
T
Fukui
Rie
R
Kizawa
Kazuo
K
Kozaki
Tsukasa
T
Sanzen
Takahiro
T
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D003307:Copulation / Q000187:drug effects; D004334:Drug Administration Schedule; D004435:Eating / Q000187:drug effects; D010064:Embryo Implantation / Q000187:drug effects; D004622:Embryo, Mammalian / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D007564:Japan; D008136:Longevity / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D006080:Ovarian Follicle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000187:drug effects* / Q000473:pathology; D011247:Pregnancy; D055818:Public-Private Sector Partnerships; D051381:Rats; D017207:Rats, Sprague-Dawley; D012958:Societies, Scientific; D018675:Toxicity Tests / Q000379:methods*; D014599:Uterus / Q000187:drug effects / Q000473:pathology; D014621:Vagina / Q000187:drug effects / Q000473:pathology
D000970:Antineoplastic Agents; D002945:Cisplatin