Developmental toxicity studies of 2-(difluoromethyl)-dl-ornithine (DFMO) in rats and rabbits

DFMO, an irreversible inhibitor of ornithine decarboxylase (ODC), is under development as a chemopreventive drug against cancers with pronounced proli ferative phases. In support of human clinical trials, preclinical developme ntal toxicity studies were conducted in pregnant rats and rabbits. Rats wer e treated during GD 6-17, and fetuses were obtained by C-section on GD 20. Rabbits were treated during GD 7-20, and fetuses were obtained by C-section on GD 29. The dose range-finding study in rats (5/group at 0, 50, 125, 300 , 800, or 1000 mg/kg/day) revealed maternal toxicity at doses greater than or equal to 800 mg/kg/day (decreased body weights and food consumption) and developmental toxicity at doses greater than or equal to 300 mg/kg/day (in creased early resorptions and reduced fetal body weights). In the main stud y, rats (25/group) received 0, 30, 80, or 200 mg/kg/day. Developmental toxi city in the absence of maternal toxicity was observed at 200 mg/kg/day as s ignificantly decreased fetal weights and increased incidence of litters wit h skeletal variations of 14th rudimentary rib, 14th full rib, and/or 27th p resacral vertebrae. There were no treatment-related fetal skeletal malforma tions or external or visceral anomalies at any dose level. The dose range-f inding study in rabbits (5/group at 0, 30, 60, 120, 240, or 500 mg/kg/day) revealed developmental toxicity at doses greater than or equal to 60 mg/kg/ day (increased resorptions and reduced fetal body weights) in the absence o f maternal toxicity. In the main study, rabbits (20/group) received 0, 15, 45, or 135 mg/kg/day. Developmental toxicity in the absence of maternal tox icity was observed at 135 mg/kg/day as nonsignificantly increased early res orptions, decreased implantation sites, decreased viable fetuses, and reduc ed fetal weights. There were no external, visceral, or skeletal anomalies a t any dose level. Thus, in the main developmental toxicity studies, DFMO pr oduced developmental but not maternal toxicity at 200 and 135 mg/kg/day in rats and rabbits, respectively. Accordingly, in rats, the maternal no-obser vable-effect level (NOEL) was 200 mg/kg/day and the fetal NOEL was 80 mg/kg /day; while in rabbits the maternal NOEL was 135 mg/kg/day and the fetal NO EL was 45 mg/kg/day. These fetal NOELs are several-fold higher than the dos e level currently used in Phase II and III clinical trials (similar to 13 m g/kg).