Chronic toxicity studies of the potential cancer preventive 2-(difluoromethyl)-dl-ornithine.
The synthetic compound 2-(difluoromethyl)-dl-ornithine irreversibly inhibits ornithine decarboxylase and reduces the intracellular levels of the polyamine cell cycle factors putrescine and spermidine. The drug has shown chemopreventive efficacy in numerous laboratory epithelial cancer models and is a prototype for antiproliferative agents. Chronic toxicity studies in rats and dogs were performed to characterize the toxicities of the compound at high dosages and to support its further development in clinical trials as a potential chemopreventive agent. Chronic administration (52 weeks) by gavage to Charles River CD rats at dosages of 400, 800, and 1600 mg/kg produced weight loss, increased platelets, alopecia and skin abrasions, dermatitis, liver necrosis, and gastric inflammation. The no-effect dose in this study was considered 400 mg/kg. Chronic administration by capsule to dogs at dosages of 50, 100, and 200 mg/kg produced conjunctivitis, hyperkeratosis and alopecia, and cystic intestinal crypts. A no-effect dose was not determined in this study. The toxicities demonstrated in these studies may be minimized at lower dosages and support the further development of this compound in chemopreventive clinical investigations.
Crowell
J A
JA
Chemoprevention Branch, National Cancer Institute, Bethesda, Maryland 20892.
Goldenthal
E I
EI
Kelloff
G J
GJ
Malone
W F
WF
Boone
C W
CW
D000818:Animals; D016588:Anticarcinogenic Agents / Q000633:toxicity*; D001772:Blood Cell Count / Q000187:drug effects; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D003231:Conjunctivitis / Q000139:chemically induced / Q000473:pathology; D003872:Dermatitis / Q000473:pathology; D004285:Dogs; D004435:Eating / Q000187:drug effects; D000518:Eflornithine / Q000633:toxicity*; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D012727:Sex Characteristics; D012867:Skin / Q000473:pathology; D013045:Species Specificity
D016588:Anticarcinogenic Agents; D006454:Hemoglobins; D000518:Eflornithine