Chemoprevention of second primary cancer in the patients with lung cancer

早期非小细胞肺癌和小细胞肺癌患者的继发性肺癌风险估计分别为1-2%和2-10%。令人惊讶的是，局部晚期非小细胞肺癌在顺铂化疗联合放疗后10年的第二原发癌发病率增加到61%。这些患者在治愈的道路上，不能忽视发展第二原发癌的可能性。我们在A/J小鼠中使用顺铂作为致癌物开发了第二原发性肺癌模型，以筛选第二恶性肿瘤的化学预防剂。在原发性肺肿瘤模型中，4-（甲基-亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）、苯并（a）芘（BaP）、乌拉坦分别在A/J小鼠中诱导密码子12、密码子13和密码子61的特异性K-ras突变。在这项研究中，我们研究了顺铂在A/J小鼠中的致癌性机制。在顺铂诱导的肿瘤中，我们没有发现K-ras密码子12突变，这是NNK或BaP诱导的主要突变。K-ras基因第13位密码子和第61位密码子突变分别在1例（4%）和5例（17.8%）肿瘤中发现。这些结果表明顺铂与K-ras基因第61位密码子突变部分相关，顺铂的致癌机制与NNK或BaP不同

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 13, 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 5 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