Effects of eflornithine hydrochloride (DFMO) on fetal development in rats and rabbits.
Eflornithine hydrochloride (DFMO) is a highly selective, enzyme-activated, irreversible inhibitor of the enzyme L-ornithine decarboxylase (ODC). Because of its role in the biosynthetic pathway of polyamines, ODC is essential for the growth and development of newly implanted embryonic tissue. In order to assess its effect on embryonic growth and fetal development, at various stages of gestation, DFMO was administered in the drinking water to pregnant rats and rabbits at several concentrations (from 0.03% to 3.0%) and times (from days 7, 10, or 11 through days 18 or 19). Rats were killed on day 21 and rabbits on day 29 of pregnancy (day 1 = day of insemination), and the implantations and fetuses were examined. At a concentration of 1.0% (approximately 1,270 mg/kg/day) in rats and 3.0% (approximately 915 mg/kg/day) in rabbits, maternal food and water consumption and body weight gain were significantly reduced during the treatment period, and all implantations were aborted or resorbed. At lower doses (approximately 200-600 mg/kg/day) fetuses survived to term, though in reduced numbers, and a marked reduction in average fetal weight was seen. At levels of 60 mg/kg/day or lower, there were no deleterious effects to the dams or their offspring. Few malformations were detected at any dose level by gross teratologic examination; nor were any considered to have been drug induced because of their sporadic incidence. The embryotoxicity and severe growth retardation demonstrated by these studies verify that adequate polyamine levels are essential for normal embryonic and fetal development.
O'Toole
B A
BA
Department of Pathology-Toxicology, Merrell Dow Research Institute, Merrell Dow Pharmaceuticals, Inc., Cincinnati, Ohio 45215.
Huffman
K W
KW
Gibson
J P
JP
D000014:Abnormalities, Drug-Induced; D000022:Abortion, Spontaneous / Q000139:chemically induced; D000818:Animals; D004305:Dose-Response Relationship, Drug; D000518:Eflornithine / Q000633:toxicity*; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D011073:Polyamines / Q000502:physiology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011817:Rabbits; D051381:Rats
D011073:Polyamines; D000518:Eflornithine