Chemopreventive effects of gefitinib on nonsmoking-related lung tumorigenesis in activating epidermal growth factor receptor transgenic mice.
Twenty-five percent of all lung cancer cases are not attributable to smoking. Epidermal growth factor receptor (EGFR) mutations, which are involved in approximately 50% of nonsmoker lung cancer, are positively correlated with responsiveness to gefitinib, and inversely correlated with smoking history. Activating EGFR mutations play a critical role in the carcinogenesis of nonsmoking-related lung cancer. To investigate the chemopreventive effects of gefitinib on nonsmoking-related lung cancer, we generated transgenic mice expressing EGFR L858R in type II pneumocytes constitutively using the surfactant protein-C promoter. The transgenic mice invariably developed atypical adenomatous hyperplasia at age 4 weeks and multifocal adenocarcinoma of varying sizes at age 7 weeks. Notably, the expression levels of phosphorylated and total ErbB2, ErbB3, and thyroid transcription factor-1 were elevated in the transgenic mice compared with wild-type controls at age 3 weeks. Administration of gefitinib to 3-week-old transgenic mice for 1 week before carcinogenesis reduced the amount of phosphorylated EGFR in the lungs of the mice to the baseline level. Gefitinib (5 mg/kg/d; n = 5, 5, and 15) or vehicle (n = 5, 5, and 15) was administered to transgenic mice from age 3 to 8, 13, and 18 weeks, respectively. The numbers of lung tumors in the control and gefitinib-treated groups were 1.75, 5.8, 10.2, and 0 (P < 0.05), respectively. No fatal toxic events occurred in either group, and gefitinib inhibited tumorigenesis completely in this mouse model. These results suggest the utility of molecular targeted chemoprevention against nonsmoking-related lung cancer.
Ohashi
Kadoaki
K
Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Takigawa
Nagio
N
Osawa
Masahiro
M
Ichihara
Eiki
E
Takeda
Hiromasa
H
Kubo
Toshio
T
Hirano
Seiki
S
Yoshino
Tadashi
T
Takata
Minoru
M
Tanimoto
Mitsune
M
Kiura
Katsuyuki
K
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D037721:Pulmonary Surfactant-Associated Protein C; D011799:Quinazolines / Q000494:pharmacology*; D020893:Receptor, ErbB-3 / Q000235:genetics; D012907:Smoking
D000970:Antineoplastic Agents; D037721:Pulmonary Surfactant-Associated Protein C; D011799:Quinazolines; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D000077156:Gefitinib