Genetic alterations in K-ras and p53 cancer genes in lung neoplasms from Swiss (CD-1) male mice exposed transplacentally to AZT
Genetic alterations in K-ras and p53 cancer genes in lung neoplasms from Swiss (CD-1) male mice exposed transplacentally to AZT
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DOI：
10.1002/em.20197
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发表时间：
2007-04-01
影响因子：
2.8
通讯作者：
Sills, Robert C.
中科院分区：
文献类型：
--
作者：
Hong, Hue-Hua L.;Dunnick, June;Sills, Robert C.
一项经胎盘致癌研究是通过将怀孕的瑞士(CD-1)小鼠暴露于0、50、100、200或300毫克的3‘-叠氮-3’-脱氧胸苷(AZT)/kg bw，在妊娠18至19天期间进行的[国家毒理学计划，NIH Pub。2004年第04-4458号]。200 mg/kg和300 mg/kg剂量组小鼠肺泡/细支气管腺瘤和癌的发生率显著高于对照组。在目前的研究中，我们从这种生物检测中评估了良性和恶性肺部肿瘤的点突变，K-ras和p53癌基因在人类肺癌中经常发生突变。从福尔马林固定的石蜡包埋肿瘤中分离出多聚糖链式反应扩增的DNA，通过循环测序检测K-ros和p53突变。在38例AZT诱发的肺肿瘤中，有25例(66%)检测到K-ros基因突变，其中以第12位密码子G-T颠换为主。在38例AZT诱发的肺肿瘤中，32例(84%)检测到P53基因突变，其中以外显子8、密码子285 A-T颠换和外显子6、密码子198 T-A颠换为主。在对照小鼠的五个肿瘤中没有检测到K-ros或p53突变。肺肿瘤中发现的突变模式表明，AZT或其代谢产物掺入DNA、氧化应激和基因组不稳定可能是这些小鼠肺癌突变和发展的促成因素。环境。马尔。诱变剂。48：299-306,2007。2006年出版，Wiley-Liss，Inc.
A transplacental carcinogenicity study was conducted by exposing pregnant Swiss (CD-1) mice to 0, 50, 100, 200, or 300 mg of 3'-azido-3'-deoxythymidine (AZT)/kg bw/day, through a 18 to 19 day gestation [National Toxicology Program, NIH Pub. No. 04-4458, 2004]. The incidences of alveolar/bronchiolar adenomas and carcinomas, in the 200 and 300 mg/kg male treatment groups, were significantly greater than that of the controls. In the present study, we evaluated the benign and malignant lung neoplasms from this bioassay for point mutations, in the K-ras and p53 cancer genes that are often mutated in human lung tumors. K-ros and p53 mutations were detected by cycle sequencing of polymerose chain reaction-amplified DNA, isolated from formalin-fixed, paraffin-embedded neoplasms. K-ros mutations were detected in 25 of 38 (66%) of the AZT-induced lung tumors, and the predominant mutations were codon 12 G-T transversions. p53 mutations were detected in 32 of 38 (84%) of the AZT-induced lung tumors, with the predominant mutations being exon 8, codon 285 A-T transversions, and exon 6, codon 198 T-A transversions. No K-ros or p53 mutations were detected in five tumors, examined from control mice. The patterns of mutations identified in the lung tumors suggest that incorporation of AZT or its metabolites into DNA, oxidative stress, and genomic instability may be the contributing factors to the mutation profile and development of lung cancer in these mice. Environ. Mal. Mutagen. 48:299-306, 2007. Published 2006 Wiley-Liss, Inc.