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

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).

α‐Difluoromethylornithine, a polyamine inhibitor: its potential role in controlling hair growth and in cancer treatment and chemo‐prevention

“…The topical cream is applied twice daily within 2 h of shaving, and a topical application of 0.5 g twice daily resulted in approximately 100-to six-fold lower doses compared to a once-a-day oral dose of 370 mg. 4 DFMO appeared to arrest embryonic development during the peri-implantation period, however. 73 Marked improvement was seen consistently at 8 weeks after the initiation of treatment and continued throughout the 24 weeks of treatment.…”

“…In clinical trials of women who removed facial hair two or more times per week, statistically significant decreased hair growth was observed with VANIQA vs. vehicle in all studies. 4 Eflornithine hydrochloride cream is a pregnancy category C drug, and caution is advised in nursing women. Hair growth approached pretreatment levels within 8 weeks of treatment withdrawal.…”

“…Cellular polyamines have a major effect on growth, differentiation, and apoptosis. 4 Polyamine synthesis occurs during the G1 phase of the cell cycle, and an increase in polyamine levels occurs with cell transformation and/or proliferation induced by growth factor stimulation or by carcinogens, viruses, or oncogenes. 2 The polyamines generated stimulate DNA, RNA, and protein synthesis, and bind to DNA, RNA, phospholipids, membranes, and cytoskeletal structures, modulating their susceptibility to endogenous stresses as well as their structures during proliferation.…”

“…3 Quiescent cells display low ODC activity, whereas mitogenic triggering induces a rapid upregulation of ODC activity. 1,4 Although multiple factors increase the expression of ODC, Myc and Fos are the primary proto-oncogenes that activate ODC by transcription. 1,2 The polyamines, putrescine, spermidine, and spermine, are present in all mammalian cells.…”

Polyamines protect rat embryo in vitro from high glucose‐induced developmental delay and dysmorphogenesis

“…Administration of a selective ODC inhibitor, DLa-difluoromethyl-ornithine, to pregnant rats and rabbits during organogenesis produces developmental delay, decrease in fetal weight, and pregnancy loss, in a dosedependent manner, but does not produce malformations or maternal toxicity (O'Toole et al, 1989;Kirchner et al, 1999), indicating that an adequate supply of polyamines is required for healthy development during organogenesis and neurulation. This supply is compromised in diabetic rat embryos and it has been reported that ODC activity and polyamine concentrations are dramatically reduced in them during these processes in comparison with those found in equivalent rat embryos of normoglycemic dams (Bengtsson et al, 1994).…”