4-Ipomenaol (IPO) has been shown to induce P-450-mediated
necrosis of Clara cells in experimental animals, and clinical trials were initiated to treat people with bronchioloalveolar
cancers with this novel
drug. We therefore performed experiments to examine two different animal lung
tumor models for acute IPO cytotoxicity: hamster Clara-cell-derived
adenocarcinomas and mouse alveolar type II cell
tumors. Clara cells serve as stem cells for airway cell renewal and, therefore,
tumors derived from Clara cells may likewise differentiate into various bronchiolar cell types, or undergo squamous cell
metaplasia. Bronchiolar cell
tumors were induced in Syrian hamsters by a single weekly gavage with 6.8 mg
N-nitrosomethyl-n-heptylamine (NMHA)/animal for 35 weeks. NMHA-induced bronchiolar
tumors were classified as well-differentiated lepidic
bronchioloalveolar carcinomas, acinar
adenocarcinoma,
adenosquamous carcinoma, and
squamous-cell carcinoma. After 35 and 46 experimental weeks, control and
carcinogen-treated hamsters were injected once with doses of 40-110 mg IPO/kg i.p. and necropsied 15-48 h later. Solid and papillary
tumors with alveolar cell features were induced transplacentally in C3H/HeNCr mice, by treating pregnant animals on gestation day 16 with 0.5 mmol N-
nitrosoethylurea/kg, i.p. Offspring of control and
carcinogen-treated mice were injected at 2-3 months of age with 35 mg or 50 mg IPO/kg i.p. and necropsied either 24-48 h or 5 and 12 days after injection. Light microscopic studies were carried out to assess cytotoxic effects in various tissues in both hamsters and mice; in hamsters, additional ultrastructural studies were performed. When administered to hamsters, IPO induced moderate to severe cytotoxicity in normal and dysplastic bronchiolar lining cells, in most lepidic
bronchioloalveolar carcinomas, and in some glandular areas of adenosquamous cell
carcinomas. Susceptible cells included normal, anaplastic, and neoplastic nonciliated and some ciliated bronchiolar cells. Undifferentiated and squamous
tumor cells were resistant to IPO, as were resident normal alveolar type II cells. However, some
adenocarcinomas composed primarily of ciliated and mucous cells also showed no IPO-induced
necrosis, indicating a deficiency in appropriate activating
enzymes. In the mice, IPO induced bronchiolar cell
necrosis and, at the high dose, also severe
pulmonary edema. No cytotoxicity was observed in normal or hyperplastic alveolar epithelium, nor in either solid or papillary growth forms of mouse alveolar cell
tumors.(ABSTRACT TRUNCATED AT 400 WORDS)