Chung Moon-Koo, Kim Choong-Yong, Kim Jong-Choon
Korea Institute of Toxicology, KRICT, Yuseong, Daejeon, 305-600, South Korea.
Cancer Chemother Pharmacol. 2007 Feb;59(3):383-95. doi: 10.1007/s00280-006-0290-x. Epub 2006 Aug 1.
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.
CKD - 602是一种喜树碱类抗癌药物，由韩国崇坤堂制药公司（首尔）近期研发。本研究考察了CKD - 602对雌性斯普拉格 - 道利大鼠妊娠、分娩和哺乳的潜在不良影响，以及对其后代出生前后发育的影响。100只怀孕雌性大鼠被分为四组：三个治疗组和一个对照组。从妊娠第6天起，通过静脉推注，以0、5.7、17或51微克/千克/天的剂量，每天给雌性大鼠注射一次CKD - 602，直至分娩，并在整个哺乳期直至断奶（哺乳第21天）。所有母鼠在断奶后的哺乳第22天处死。对其后代的临床体征、死亡率、体重变化、食物消耗量、身体发育和行为功能进行评估。当暴露的后代达到成熟（出生后第70天）时，评估其生殖性能。在高剂量组中，在妊娠和哺乳期的母鼠中均观察到体重受到抑制和食物消耗量减少。在预定的尸检中，还观察到母鼠胸腺萎缩发生率增加、肝脏和卵巢重量减轻以及脾脏重量增加。此外，在F1代后代中观察到死产数量和出生后死亡率增加、活产仔数减少以及身体发育延迟。致畸检查显示F1代后代和F2代胎儿中先天性异常的发生率增加。在中剂量组中，仅观察到包括体重受抑制和食物消耗量减少在内的轻微母体毒性。低剂量组中未观察到与治疗相关的对母体功能以及出生前后发育的影响。CKD - 602对母鼠的未观察到有害作用水平（NOAEL）被认为是5.7微克/千克/天，然而，对其后代的NOAEL估计为17微克/千克/天。
