K-RAS AND P53 POINT MUTATIONS IN 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANNONE-INDUCED HAMSTER LUNG-TUMORS
K-RAS AND P53 POINT MUTATIONS IN 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANNONE-INDUCED HAMSTER LUNG-TUMORS
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DOI：
10.1093/carcin/14.3.451
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发表时间：
1993-03-01
期刊：
影响因子：
4.7
通讯作者：
WITSCHI, H
中科院分区：
文献类型：
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作者：
OREFFO, VIC;LIN, HW;WITSCHI, H
在叙利亚金仓鼠中通过皮下注射诱导肺肿瘤。注射4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）。40周后，分离肺肿瘤组织。施用NNK并将动物暴露于65%氧气的气氛导致肿瘤大小的统计学显著减小，但与保持在环境空气下的致癌物处理的动物相比，没有改变组织学肿瘤类型或肿瘤发生率。组织学上，肺肿瘤具有腺瘤和腺癌的形态特征，其中约15%为鳞状细胞癌。通过直接测序检测肺肿瘤中Ki-ras癌基因和p53肿瘤抑制基因的突变。从合并的肿瘤中分离的RNA和从单个肿瘤中分离的DNA中的Ki-ras突变频率被发现是相同的。在77 - 94%的肿瘤中检测到活化的Ki-ras等位基因。观察到的所有突变（总共65个）中，除了一个是GC-AT。Ki-ras突变导致密码子12或13处的氨基酸取代。在第61位密码子处未检测到突变。对相同肿瘤的p53突变检查仅显示一个点突变。我们的结论是，NNK治疗在叙利亚金黄地鼠的结果在Ki-ras基因的一个独特的突变模式，而p53基因突变可能不会发挥重要作用，在这个阶段在仓鼠肺肿瘤发生。
Lung tumors were induced in Syrian golden hamsters by s.c. injection of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). After 40 weeks lung tumor tissue was isolated. Administration of the NNK and exposure of the animals to an atmosphere of 65% oxygen resulted in a statistically significant reduction in tumor size but did not alter the histological tumor type or tumor incidence when compared with carcinogen treated animals maintained under ambient air. Histologically, lung tumors had the morphologic features of adenomas and adenocarcinomas with approximately 15% being squamous cell carcinomas. Lung tumors were examined for mutations in the Ki-ras oncogene and the p53 tumor suppressor gene by direct sequencing. The Ki-ras mutation frequency in RNA isolated from pooled tumors and in DNA isolated from individual tumors were found to be identical. Activated Ki-ras alleles were detected in 77 - 94% of tumors. All mutations observed (from a total of 65) except one were GC-AT. The Ki-ras mutations resulted in amino acid substitutions at either codons 12 or 13. No mutations were detected at the 61st codon. Examination of the same tumors for p53 mutations showed only one point mutation. We conclude that the NNK treatment in Syrian golden hamsters results in a distinctive mutation pattern in the Ki-ras gene whereas p53 gene mutations may not play a major role at this stage in hamster lung tumorigenesis.