Morales Cristina, Ribas Maria, Aiza Gemma, Peinado Miguel A
IDIBELL-Institut de Recerca Oncològica, Granvia km 2,7, L'Hospitalet, 08907 Barcelona, Spain.
Oncogene. 2005 Oct 13;24(45):6842-7. doi: 10.1038/sj.onc.1208834.
Alternative genetic pathways characterized by specific genetic profiles and exhibiting distinctive biological and clinical features have been proposed in colorectal carcinogenesis. Methotrexate (MTX) is a potent inhibitor of the dihydrofolate reductase (DHFR) enzyme, which is essential for DNA synthesis and cell growth. We have evaluated the association between different genetic features and the capacity to develop MTX resistance in colon cancer cell lines representative of alternative genetic pathways. Three aneuploid cell lines (HT-29, SW480, and SK-CO-1) showed pre-existing amplifications, but only one (HT-29) developed MTX resistance, showing amplification of the DHFR gene at 5q12-14 (>20-fold amplification and presence of extrachromosomal double minutes). Failure to develop resistance was attributed to the absence of two complete chromosomes 5 in SW480 and SK-CO-1 cells. Four near-diploid cell lines (LoVo, HCT116, DLD-1 and KM12C) and two aneuploid KM12C-derived metastases (KM12SM and KM12L4A) developed MTX resistance but none exhibited DHFR amplification. All resistant cells without DHFR gene amplification showed microsatellite instability. We conclude that chemoresistance capacity and the mechanism of chemoresistance are related with the genetic pathway and the karyotypic features of colon cancer cells.
在结直肠癌发生过程中，已提出了以特定基因谱为特征并表现出独特生物学和临床特征的替代遗传途径。甲氨蝶呤（MTX）是二氢叶酸还原酶（DHFR）的有效抑制剂，而DHFR对于DNA合成和细胞生长至关重要。我们评估了不同遗传特征与代表替代遗传途径的结肠癌细胞系中产生MTX耐药性的能力之间的关联。三个非整倍体细胞系（HT-29、SW480和SK-CO-1）显示出预先存在的扩增，但只有一个（HT-29）产生了MTX耐药性，在5q12-14处显示出DHFR基因扩增（>20倍扩增且存在染色体外双微体）。未能产生耐药性归因于SW480和SK-CO-1细胞中不存在两条完整的5号染色体。四个近二倍体细胞系（LoVo、HCT116、DLD-1和KM12C）以及两个源自非整倍体KM12C的转移瘤（KM12SM和KM12L4A）产生了MTX耐药性，但均未表现出DHFR扩增。所有未发生DHFR基因扩增的耐药细胞均表现出微卫星不稳定性。我们得出结论，化疗耐药能力和化疗耐药机制与结肠癌细胞的遗传途径和核型特征有关。
