Acute effects of 4-ipomeanol on experimental lung tumors with bronchiolar or alveolar cell features in Syrian hamsters or C3H/HeNCr mice.
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)
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Laboratory of Comparative Carcinogenesis, National Cancer Institute, NCI/FCRDC, Frederick, Maryland 21702-1201.
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D000230:Adenocarcinoma / Q000188:drug therapy; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D018196:Carcinoma, Adenosquamous / Q000188:drug therapy; D006224:Cricetinae; D005260:Female; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008809:Mice, Inbred C3H; D013729:Terpenes / Q000009:adverse effects / Q000494:pharmacology*
D000970:Antineoplastic Agents; D013729:Terpenes; C001470:4-ipomeanol