Reproductive toxicity evaluation of a new camptothecin anticancer agent, CKD-602, in pregnant/lactating female rats and their offspring.
CKD-602 is a camptothecin anticancer agent that was recently developed by the Chong Kun Dang Pharmaceutical Co. (Seoul, Korea). This study examined the potential adverse effects of CKD-602 on pregnancy, delivery, and lactation in female Sprague-Dawley rats as well as on the pre- and postnatal development of their offspring. One hundred pregnant females were divided into four groups: three treatment groups and a control group. CKD-602 was administered once daily by intravenous bolus injection to female rats at doses of 0, 5.7, 17, or 51 microg/kg/day from gestational day 6, through to parturition and throughout the period of lactation up to weaning [lactational day (LD) 21]. All the dams were sacrificed on LD 22 after weaning. The clinical signs, mortality, body weight change, food consumption, physical development, and behavioral function were evaluated in their progeny. When the exposed offspring reached maturity (postnatal day 70), their reproductive performance was assessed. In the high-dose group, suppressed body weight and a decrease in the amount of food consumption were observed in the dams during both the gestation and lactation periods. An increase in the incidence of thymic atrophy, decreased liver and ovary weight, and an increase in the weight of the spleen were also observed in the dams at the scheduled necropsy. In addition, an increase in the number of stillborn and postnatal mortality, a decrease in the live litter size, and a delay in physical development were observed in the F1 offspring. Teratological examinations showed an increase in the incidence of congenital anomalies in both the F1 offspring and F2 fetuses. In the medium dose group, only slight maternal toxicity including suppressed body weight and decreased food consumption was observed. There were no treatment-related effects on the maternal function and pre- and postnatal development in the low dose group. The no-observed-adverse-effect level (NOAEL) of CKD-602 for the dams are considered to be 5.7 microg/kg/day, however, the NOAEL for their offspring are estimated to be 17 microg/kg/day.
Chung
Moon-Koo
MK
Korea Institute of Toxicology, KRICT, Yuseong, Daejeon, 305-600, South Korea.
Kim
Choong-Yong
CY
Kim
Jong-Choon
JC
D000014:Abnormalities, Drug-Induced; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D000970:Antineoplastic Agents / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D007275:Injections, Intravenous; D007774:Lactation / Q000187:drug effects*; D008136:Longevity / Q000187:drug effects; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D019055:No-Observed-Adverse-Effect Level; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D013723:Teratogens / Q000633:toxicity*
D000970:Antineoplastic Agents; D013723:Teratogens; C116963:belotecan; D002166:Camptothecin