Point mutation of K-ras gene in cisplatin-induced lung tumours in A/J mice.
The risks of secondary lung cancer in patients with early stage non-small and small cell lung cancers are estimated to be 1-2% and 2-10% per patient per year, respectively. Surprisingly, the incidence of second primary cancer in locally advanced non-small cell lung cancer at 10 years, following cisplatin-based chemotherapy with concurrent radiotherapy, increases to 61%. Those patients, on the road to being cured, cannot overlook the possibility of developing a second primary cancer. We developed a second primary lung cancer model using cisplatin as a carcinogen in A/J mice to screen for chemopreventive agents for a second malignancy. In the primary lung tumour model, 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), benzo(a)pyrene (BaP), urethane induces specific K-ras mutations in codon 12, codon 12, and codon 61, respectively, in the A/J mice. In this study, we investigated the mechanisms of carcinogenicity by cisplatin in the A/J mice. In the cisplatin-induced tumours, we found no K-ras codon 12 mutation, which is the major mutation induced by NNK or BaP. K-ras gene mutations in codon 13 and codon 61 were found in one tumour (4%) and five tumours (17.8%), respectively. These findings suggest that cisplatin is partially related to K-ras codon 61 mutations, and that the mechanism of carcinogenicity by cisplatin is different from that by NNK or BaP.
Hisamoto
Akiko
A
Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Kondo
Eisei
E
Kiura
Katsuyuki
K
Okada
Toshiaki
T
Hosokawa
Shinobu
S
Mimoto
Junko
J
Takigawa
Nagio
N
Tabata
Masahiro
M
Tanimoto
Mitsune
M
D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D002289:Carcinoma, Non-Small-Cell Lung / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D002945:Cisplatin / Q000009:adverse effects / Q000633:toxicity*; D003062:Codon; D005260:Female; D011905:Genes, ras; D008175:Lung Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D016609:Neoplasms, Second Primary / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000517:prevention & control; D009602:Nitrosamines / Q000633:toxicity; D017354:Point Mutation
D002273:Carcinogens; D003062:Codon; D009602:Nitrosamines; D001564:Benzo(a)pyrene; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D002945:Cisplatin