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继发性肺癌的风险估计分别为每位患者每年1-2%和2-10%。令人惊讶的是，局部晚期非小细胞肺癌患者在顺铂化疗合并放疗后10年的第二原发癌发生率增加到61%。在治愈的道路上，这些患者不能忽视患第二原发癌症的可能性。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药物。在原发性肺肿瘤模型中，4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK），苯并(a)芘（BaP），聚氨酯分别在a /J小鼠的密码子12，密码子13和密码子61中诱导特异性K-ras突变。本研究探讨顺铂对A/J小鼠的致癌性机制。在顺铂诱导的肿瘤中，我们未发现K-ras密码子12突变，这是NNK或BaP诱导的主要突变。K-ras基因密码子13突变1例（4%），密码子61突变5例（17.8%）。这些发现提示顺铂与K-ras密码子61突变部分相关，顺铂的致癌性机制不同于NNK或BaP

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