belotecan and Abnormalities--Drug-Induced

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.

Topics: Abnormalities, Drug-Induced; Animals; Animals, Newborn; Antineoplastic Agents; Behavior, Animal; Body Weight; Camptothecin; Dose-Response Relationship, Drug; Eating; Embryonic Development; Female; Fetal Development; Injections, Intravenous; Lactation; Longevity; Male; Maternal Exposure; No-Observed-Adverse-Effect Level; Pregnancy; Rats; Rats, Sprague-Dawley; Reproduction; Teratogens

This study examined the potential adverse effects of a new camptothecin anticancer agent, CKD-602, on the fertility and early embryonic development of Sprague-Dawley rats. Ninety-six rats of each gender were divided into four groups: three treatment groups and a control group. CKD-602 was administered intravenously to male rats at 0, 4.7, 14, and 42 microg/kg from 63 days prior to mating until the end of the mating period, and to female rats from 14 days before mating until day 6 of gestation. All the males were sacrificed after the end of the 14-day mating period, while all the females were subjected to a caesarean section on day 15 of gestation. In the high dose group, a high incidence of hair loss was observed in both genders. A decrease in the level of food consumption, followed by a decrease in body weight gain was also observed in both genders. At the scheduled necropsy, the gross postmortem examinations revealed an increase in the incidence of thymic atrophy, paleness of the thoracic and abdominal organs in both genders and an increase in the serum testosterone concentration. In addition, there was a decrease in the thymus weight of the males and an increase in the liver, spleen, kidneys, lung, and heart weights of the females. There was an increase in the number of fetal deaths and post-implantation losses as well as a decrease in the litter size found at the caesarean section of the dams. No treatment-related effect on the histopathological findings, sexual cycle, pre-coital time, mating index, fertility index, pregnancy index, and sperm parameters was observed. There were no adverse effects on the general findings and reproductive performance of the parent animals and early embryonic development in the low and medium dose groups. Overall, the no-observed-adverse-effect levels (NOAELs) of CKD-602 are believed to be 14 microg/kg for both general toxicity and early embryonic development, and more than 42 microg/kg for the reproductive performance of the parent animals.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Body Weight; Camptothecin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Embryonic Development; Female; Fertility; Injections, Intravenous; Litter Size; Male; No-Observed-Adverse-Effect Level; Organ Size; Rats; Rats, Sprague-Dawley

CKD-602 is a newly developed camptothecin anticancer agent. Preclinical studies suggest that it may have greater antitumor activity and lower toxicity than other camptothecin anticancer agents. The potential of CKD-602 to induce developmental toxicity was investigated in the New Zealand White rabbit. Seventy-two artificially inseminated females (artificial insemination=day 0) were distributed among three treatment groups and a control group. CKD-602 was at dose levels of 0, 0.024, 0.048, or 0.096 mg x kg(-1) x day(-1) administered intravenously to pregnant does from days 6 to 18 of gestation. All does were subjected to caesarean section on day 28 of gestation. At 0.096 mg x kg(-1) x day(-1), 2 cases of abortion and 3 cases of death in pregnant rabbits were found in late gestation. In addition, an increase in the embryonic resorptions and a decrease in the litter size were found. At 0.048 mg x kg(-1) x day(-1), a single doe aborted on gestational day 26. An increase in the embryonic resorptions and fetal morphological alterations and a decrease in the litter size were also found. There were no signs of maternal toxicity or developmental toxicity at 0.024 mg x kg(-1) x day(-1). The results show that 13-day repeated intravenous dose of CKD-602 during the major organogenetic period in rabbits produces increased incidence of abortion and death, increased number of embryonic resorptions and fetal morphological alterations, and decreased litter size at dose levels of above 0.048 mg x kg(-1) x day(-1). In the current experimental conditions, the no-observed-adverse-effect levels (NOAELs) of CKD-602 are considered to be 0.048 mg x kg(-1) x day(-1) for does and 0.024 mg x kg(-1) x day(-1) for embryo-fetal development.

Topics: Abnormalities, Drug-Induced; Animals; Antineoplastic Agents, Phytogenic; Camptothecin; Dose-Response Relationship, Drug; Embryo Loss; Female; Fetal Resorption; Injections, Intravenous; Litter Size; No-Observed-Adverse-Effect Level; Pregnancy; Rabbits; Teratogens; Topoisomerase I Inhibitors