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Developmental toxicity studies of 2-(difluoromethyl)-dl-ornithine (DFMO) in rats and rabbits
D L Kirchner1, M D Mercieca, J A Crowell
1Toxicology Research Laboratory, University of Illinois at Chicago, 60612, USA.
Abstract:
DFMO, an irreversible inhibitor of ornithine decarboxylase (ODC), is under development as a chemopreventive drug against cancers with pronounced proliferative phases. In support of human clinical trials, preclinical developmental toxicity studies were conducted in pregnant rats and rabbits. Rats were 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 > or = 800 mg/kg/day (decreased body weights and food consumption) and developmental toxicity at doses > or = 300 mg/kg/day (increased early resorptions and reduced fetal body weights). In the main study, rats (25/group) received 0, 30, 80, or 200 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 200 mg/kg/day as significantly decreased fetal weights and increased incidence of litters with skeletal variations of 14th rudimentary rib, 14th full rib, and/or 27th presacral vertebrae. There were no treatment-related fetal skeletal malformations or external or visceral anomalies at any dose level. The dose range-finding study in rabbits (5/group at 0, 30, 60, 120, 240, or 500 mg/kg/day) revealed developmental toxicity at doses > or = 60 mg/kg/day (increased resorptions and reduced fetal body weights) in the absence of 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 toxicity was observed at 135 mg/kg/day as nonsignificantly increased early resorptions, decreased implantation sites, decreased viable fetuses, and reduced fetal weights. There were no external, visceral, or skeletal anomalies at any dose level. Thus, in the main developmental toxicity studies, DFMO produced developmental but not maternal toxicity at 200 and 135 mg/kg/day in rats and rabbits, respectively. Accordingly, in rats, the maternal no-observable-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 NOEL was 45 mg/kg/day. These fetal NOELs are several-fold higher than the dose level currently used in Phase II and III clinical trials (approximately 13 mg/kg).
Insights
DFMO (difluoromethylornithine) shows developmental toxicity in rats and rabbits at high doses, but not maternal toxicity. The no-observable-effect levels for fetal development are significantly higher than current clinical trial doses.
Area of Science:
- Toxicology
- Pharmacology
- Developmental Biology
Background:
- DFMO (difluoromethylornithine) is an irreversible ornithine decarboxylase inhibitor.
- It is being developed as a chemopreventive agent for proliferative cancers.
- Preclinical developmental toxicity studies are essential to support human clinical trials.
Purpose of the Study:
- To assess the developmental toxicity of DFMO in pregnant rats and rabbits.
- To determine the no-observable-effect levels (NOELs) for maternal and fetal toxicity.
- To compare preclinical findings with doses used in ongoing clinical trials.
Main Methods:
- Pregnant rats and rabbits were administered varying doses of DFMO during critical gestation periods.
- Maternal health, fetal development, and skeletal variations were evaluated via cesarean section.
- Dose range-finding studies informed the design of the main toxicity studies.
Main Results:
- In rats, developmental toxicity (decreased fetal weight, skeletal variations) occurred at 200 mg/kg/day without maternal toxicity.
- In rabbits, developmental toxicity (increased resorptions, decreased fetal weight) occurred at 135 mg/kg/day without maternal toxicity.
- Maternal NOELs were 200 mg/kg (rats) and 135 mg/kg (rabbits); fetal NOELs were 80 mg/kg (rats) and 45 mg/kg (rabbits).
Conclusions:
- DFMO demonstrated developmental toxicity in rats and rabbits at doses significantly higher than those used in clinical trials.
- The identified fetal NOELs suggest a substantial safety margin for current human use.
- These findings support the continued clinical investigation of DFMO for cancer chemoprevention.