Effects of erlotinib on lung injury induced by intratracheal administration of bleomycin (BLM) in rats.
Interstitial lung disease has been reported in cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors, erlotinib and gefitinib. Preclinical safety studies with erlotinib did not show any evidence for an induction of injury on intact lungs in rats and dogs. In the present study, we investigated the effects of erlotinib on lung injury induced by intratracheal administration of bleomycin (BLM) in rats. In Experiment 1, we examined the effects of short-term (7- and 21-day) administration of erlotinib (10 mg/kg/day, p.o.; subtoxic dose) on the BLM (0.1 or 0.6 mg/rat)-induced lung injury of slight and moderate severity. In Experiment 2, we examined the effects of long term (up to 63-day) administration of higher-dose (up to 20 mg/kg/day; toxic dose; accompanied with decreased body weight gain and severe skin lesions) erlotinib on the BLM-induced lung injury. In rats receiving erlotinib alone, no lung lesions were noted. In rats receiving BLM alone, diffuse alveolar damage (DAD) and, subsequently, pulmonary fibrosis of slight or moderate severity was observed. The administration of erlotinib to BLM-treated rats showed no exacerbation of lung injuries in indices such as macroscopic findings, lung weights, histopathological scores (lung lesion density and lung fibrosis score), and pulmonary hydroxyproline (HyP) level. These results suggest that erlotinib does not have any exacerbating effects on lung injuries induced by BLM in rats.
Adachi
Kenji
K
Safety Assessment Department, Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan. adachiknj@chugai-pharm.co.jp
Mizoguchi
Keiji
K
Kawarada
Shinya
S
Miyoshi
Akio
A
Suzuki
Masami
M
Chiba
Shuichi
S
Deki
Toshiaki
T
D000818:Animals; D001761:Bleomycin; D004285:Dogs; D000069347:Erlotinib Hydrochloride; D006801:Humans; D006909:Hydroxyproline / Q000032:analysis; D007267:Injections; D008168:Lung / Q000187:drug effects; D055370:Lung Injury / Q000139:chemically induced* / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000473:pathology; D011799:Quinazolines / Q000633:toxicity*; D051381:Rats; D014132:Trachea
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D001761:Bleomycin; D000069347:Erlotinib Hydrochloride; D006909:Hydroxyproline