Effects of CKD-602, a new camptothecin anticancer agent, on pregnant does and embryo-fetal development in rabbits.
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.
Chung
Moon-Koo
MK
Korea Institute of Toxicology, KRICT, Daejeon, South Korea. mkchung@kit.re.kr
Kim
Jong-Choon
JC
Han
Sang-Seop
SS
D000014:Abnormalities, Drug-Induced / Q000473:pathology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D020964:Embryo Loss / Q000139:chemically induced*; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced; D007275:Injections, Intravenous; D008098:Litter Size / Q000187:drug effects; D019055:No-Observed-Adverse-Effect Level; D011247:Pregnancy; D011817:Rabbits; D013723:Teratogens / Q000633:toxicity*; D059004:Topoisomerase I Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D013723:Teratogens; D059004:Topoisomerase I Inhibitors; C116963:belotecan; D002166:Camptothecin