Detection of Carcinogenic and Modifying Potentials by Test Compounds Using a Mouse Lung Carcinogenesis Bioassay

Abstract

Lung cancer is one of the most common cancers in the world, and the incidence of lung cancer is increasing. Therefore, it is particularly important to detect carcinogenic or tumor promoting substances of lung carcinogenesis in our environment, so that such harmful chemicals can be eliminated from our environment. Furthermore, detection of chemopreventive agents of lung carcinogenesis is also important to reduce our risk of lung cancer. It is necessary to establish reliable in vivo animal models of lung carcinogenesis for that purpose. The A/J mouse is a mouse strain sensitive to lung carcinogens, and also develops spontaneous lung tumors without any chemical treatment. In our department, we have demonstrated that a treatment of 4-(methylnitrosamino)-1-(3-pyridyle)-1-butanone (NNK), a tobacco specific nitrosamine, or 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (MeIQx), a heterocyclic amine, induced lung tumors in the female A/J mouse in 16 and 32 weeks. The lung tumors developed in the A/J mouse are histopathologically classified as adenocarcinomas, adenomas, and alveolar cell hyperplasias. Some of these types of lung cancer are similar to those of human lung cancer. We also investigated the chemopreventive effects of bovine LF (bLF) on different phases of NNK-induced lung tumorigenesis in A/J mice. The A/J mouse is very useful mouse strain as a reliable in vivo model, which can be used for detecting chemopreventive agents of lung carcinogenesis. (J Toxicol Pathol 2007; 20: 117-123)

Significance of the progesterone receptor and epidermal growth factor receptor, but not the estrogen receptor, in chemically induced lung carcinogenesis in female A/J mice

“…Previously, mutations in codon 12 of the KRAS gene were detected in carcinogen-induced rodent lung tumor models ( 31 ), with similar incidences noted to those that were previously reported during an investigation of X-ray-induced rat lung tumors ( 39 ). Various molecular studies regarding human lung cancer indicate that the notable differences in p53 and KRAS mutations are between the non - smokers and smokers.…”

“…The A/J mouse, which demonstrates increased spontaneous lung tumor development in the females than in the males, was selected for the present study. In addition, the female A/J mouse is particularly sensitive to lung carcinogenesis induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine component of tobacco smoke ( 31 ). KRAS mutations are frequently observed in this type of rodent lung carcinogenesis model, which was also noted in a case of human NSCLC ( 32 ).…”

Immunohistochemical Characteristics of Surfactant Proteins A, B, C and D in Inflammatory and Tumorigenic Lung Lesions of F344 Rats

“…Lung cancer is the leading cause of cancer-related deaths worldwide in both developing and developed regions 25 , 26 . In one study, SP-A was expressed in approximately 49% of primary non–small cell lung carcinomas 27 .…”

Different threshold levels for 2-amino-3,8 dimethylimidazo[4,5-f]quinoxaline (MelQx) initiation of lung and colon carcinogenesis and the effects of an additional initiation by 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice

“…on the other hand, proliferative lesions were induced by MeiQx in a dextran sulfate sodium model for tumor promotion, suggesting initiation activity of MeiQx in the colon (14). We also reported lung tumorigenesis for MeiQx in a/J mice (15,16), a strain which is commonly considered to be highly susceptible to the induction of lung lesions (15,17). 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (nnK) is a tobacco-specific N-nitrosamine genotoxic carcinogen with an important role in tobacco-related human lung cancer, given its strong potential to induce lung carcinogenesis in rodents (18).…”

“…We earlier reported a bioassay model for the chemoprevention of lung cancer induced by a single intraperitoneal injection (i.p.) of nnK in female a/J mice (19,15), in which lung tumors arise in almost all animals after only 13 weeks. This has clear advantages for studies on dose-dependence.…”