Bardelli A, Cahill D P, Lederer G, Speicher M R, Kinzler K W, Vogelstein B, Lengauer C
The Johns Hopkins Oncology Center, Howard Hughes Medical Institute, and Graduate Program in Human Genetics and Molecular Biology, 1650 Orleans Street, Baltimore, MD 21231, USA.
Proc Natl Acad Sci U S A. 2001 May 8;98(10):5770-5. doi: 10.1073/pnas.081082898. Epub 2001 Apr 10.
It has been proposed recently that the type of genetic instability in cancer cells reflects the selection pressures exerted by specific carcinogens. We have tested this hypothesis by treating immortal, genetically stable human cells with representative carcinogens. We found that cells resistant to the bulky-adduct-forming agent 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) exhibited a chromosomal instability (CIN), whereas cells resistant to the methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) exhibited a microsatellite instability (MIN) associated with mismatch repair defects. Conversely, we found that cells purposely made into CIN cells are resistant to PhIP, whereas MIN cells are resistant to MNNG. These data demonstrate that exposure to specific carcinogens can indeed select for tumor cells with distinct forms of genetic instability and vice versa.
最近有人提出，癌细胞中基因不稳定的类型反映了特定致癌物施加的选择压力。我们通过用代表性致癌物处理永生的、基因稳定的人类细胞来检验这一假设。我们发现，对形成大分子加合物的试剂2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）具有抗性的细胞表现出染色体不稳定性（CIN），而对甲基化试剂N-甲基-N'-硝基-N-亚硝基胍（MNNG）具有抗性的细胞表现出与错配修复缺陷相关的微卫星不稳定性（MIN）。相反，我们发现特意制成CIN细胞的细胞对PhIP具有抗性，而MIN细胞对MNNG具有抗性。这些数据表明，暴露于特定致癌物确实可以选择出具有不同形式基因不稳定的肿瘤细胞，反之亦然。
