AMPLIFICATION OF SPECIFIC DNA-SEQUENCES CORRELATES WITH MULTI-DRUG RESISTANCE IN CHINESE-HAMSTER CELLS
AMPLIFICATION OF SPECIFIC DNA-SEQUENCES CORRELATES WITH MULTI-DRUG RESISTANCE IN CHINESE-HAMSTER CELLS
复制标题
DOI：
10.1038/309626a0
复制
发表时间：
1984-01-01
期刊：
影响因子：
64.8
通讯作者：
VARSHAVSKY, A
中科院分区：
文献类型：
--
作者：
RONINSON, IB;ABELSON, HT;VARSHAVSKY, A
选择对某些细胞毒性药物具有耐药性的哺乳动物细胞，经常会对结构上与原始选择剂无关的广谱其他药物产生交叉耐药性1，2。这种现象构成了癌症化疗中的主要问题。多药耐药性源于细胞内药物积累减少1 -4，显然是由于质膜的改变2，5-7。在一些多药耐药细胞系中观察到双微小染色体或均匀染色区域8 - 12，表明基因扩增是这种现象的基础。我们使用琼脂糖凝胶中的DNA复性技术13来检测、比较和克隆中国仓鼠细胞阿霉素和秋水仙素耐药亚系中扩增的DNA序列3，12。我们发现，阿霉素和秋水仙素耐药细胞含有扩增的DNA片段，其中一些是在这两个独立的衍生细胞系扩增。此外，在不存在药物的情况下生长时多药耐药表型的丧失与扩增DNA的丧失相关。这些结果强烈表明，在多药耐药细胞系中共同扩增的DNA序列包括负责这些细胞中多药耐药的共同机制的基因。我们已经克隆了一个常见的扩增DNA片段，并表明该片段在细胞中的扩增程度与其耐药性的程度相关。
Mammalian cells selected for resistance to certain cytotoxic drugs frequently develop cross-resistance to a broad spectrum of other drugs unrelated in structure to the original selective agent1,2. This phenomenon constitutes a major problem in cancer chemotherapy. Multi-drug resistance arises from decreased intracellular drug accumulation1–4, apparently due to an alteration of the plasma membrane2,5–7. The observation of double minute chromosomes or homogeneously staining regions in some of the multi-drug-resistant cell lines8–12suggests that gene amplification underlies this phenomenon. We have used the technique of DNA renaturation in agarose gels13to detect, compare and clone amplified DNA sequences in Adriamycin- and colchicine-resistant sublines of Chinese hamster cells3,12. We show that both Adriamycin- and colchicine-resistant cells contain amplified DNA fragments, some of which are amplified in both of these independently derived cell lines. Furthermore, loss of the multi-drug resistance phenotype on growth in the absence of drugs correlates with the loss of amplified DNA. These results strongly suggest that the DNA sequences which are amplified in common in multi-drug-resistant cell lines include the gene(s) responsible for a common mechanism of multi-drug resistance in these cells. We have cloned one of the commonly amplified DNA fragments and show that the degree of amplification of this fragment in the cells correlates with the degree of their drug resistance.