Preclinical toxicology studies of 4-ipomeanol: a novel candidate for clinical evaluation in lung cancer.
4-Ipomeanol (ipomeanol) is being developed as a potential antitumor agent to treat lung cancer. Ipomeanol produced a dose-related toxicity in CD2F1 mice, Fischer 344 rats, and beagle dogs. The LD50 in mice after a single iv dose of ipomeanol was 35 mg/kg in males and 26 mg/kg in females. Minimal cumulative toxicity occurred in mice after seven doses; LD50 was 30 mg/kg/day in males and 21 mg/kg/day in females. In rats, iv doses greater than or equal to 15 mg/kg were lethal. Labored respiration, terminal bronchiolar epithelial necrosis, interstitial inflammation, and alveolar edema were present in rats dosed with ipomeanol at greater than or equal to 9 mg/kg. In addition to pulmonary lesions, splenic and thymic lymphocyte depletion and/or necrosis was present. Ipomeanol had little cumulative toxicity in rats given seven daily doses. In dogs, iv doses greater than 12 mg/kg were lethal. Dogs treated with lethal doses of ipomeanol showed rapid, shallow respiration and pulmonary edema prior to death; diffuse pulmonary congestion or hemorrhage and diffuse renal congestion were present at necropsy. Pulmonary microscopic changes caused by nonlethal doses of ipomeanol included subacute interstitial inflammation and necrosis of respiratory bronchiolar and alveolar duct epithelium. In contrast to rodents, seven daily doses of ipomeanol were cumulatively toxic in dogs. The nonlethal pulmonary effects of ipomeanol were reversible in all three species. Tolerance to lethal doses of ipomeanol occurred in animals of all three species pretreated with multiple nontoxic doses of the drug. The LD50 of ipomeanol in male and female mice increased 2.4- and 4.5-fold, respectively, in tolerant mice. In rats and dogs, previously lethal doses of 48 and 24 mg/kg were nonlethal after tolerance was induced by pretreatment with seven daily doses of ipomeanol.
Toxicology Program Office, Battelle Columbus Division, McLean, VA.
A C
AC
Smith
D
D
Barrett
M A
MA
Stedham
M
M
el-Hawari
M D
MD
Kastello
C K
CK
Grieshaber
M R
MR
Boyd
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004361:Drug Tolerance; D005260:Female; D007928:Lethal Dose 50; D008168:Lung / Q000187:drug effects; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D051381:Rats; D013729:Terpenes / Q000633:toxicity*
D000970:Antineoplastic Agents; D013729:Terpenes; C001470:4-ipomeanol