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首页> 外文期刊>Anticancer Research: International Journal of Cancer Research and Treatment >Effect of MDR1 phosphorothioate antisense oligodeoxynucleotides in multidrug-resistant human tumor cell lines and xenografts.
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Effect of MDR1 phosphorothioate antisense oligodeoxynucleotides in multidrug-resistant human tumor cell lines and xenografts.

机译：MDR1硫代磷酸酯反义寡脱氧核苷酸在多药耐药性人肿瘤细胞系和异种移植物中的作用。

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摘要

The effect of MDR1 antisense phosphorothiate oligodeoxynucleotides (S-ODNs) on resistant phenotype was investigated in multidrug-resistant human colon carcinoma and breast carcinoma cells in vitro and in vivo. Drug resistance in human colon carcinoma (SW620 Ad300) and breast carcinoma (MCF-7/INT500, MCF-7/AD150 and MCF-7/TH) cell lines is predominantly due to overexpression of P-glycoprotein (P-gp) resulting in decreased daunorubicin (DNR) accumulation. Two MDR1 antisense S-ODNs, one complementary to the initial 15 bases of first exon (S-ODN I) and the other a loop forming sequence (S-ODN II) complementary to bases from 993-1007 of MDR1 gene, were tested for enhancing the doxorubicin (DOX) cytotoxicity in vitro and the efficiency of chemotherapy in human tumor xenografts. MDR1 antisense S-ODN I reduced the DOX IC50 value 9-fold in multidrug-resistant SW620 Ad300 human colon carcinoma cells and 7 to 10-fold in breast carcinoma cells in vitro. The increase in DOX cytotoxicity correlated with a significant reduction of MDR1 mRNA in antisense S-ODN I-treated SW620 Ad300 cells. Even though the P-gp level was reduced at the end of the third day in antisense S-ODN I-treated cells, the rate of reduction was only partial compared to mRNA. The combination treatment of MDR1 antisense S-ODN I or II for three days and DOX for four days significantly controlled tumor growth rate in human tumors developed in nude mice. Our results suggest that MDR1 antisense S-ODN treatment can increase the efficiency of chemotherapy by suppressing gene expression and resistant phenotype.
机译：在体外和体内研究了多药耐药的人结肠癌和乳腺癌细胞中MDR1反义硫代磷酸酯寡聚脱氧核苷酸（S-ODN）对耐药表型的影响。人结肠癌（SW620 Ad300）和乳腺癌（MCF-7 / INT500，MCF-7 / AD150和MCF-7 / TH）细胞系中的耐药性主要是由于P-糖蛋白（P-gp）的过度表达导致柔红霉素（DNR）积累减少。测试了两个MDR1反义S-ODN，一个与第一个外显子的最初15个碱基互补（S-ODN I），另一个与MDR1基因的993-1007个碱基互补的成环序列（S-ODN II）。增强阿霉素（DOX）的体外细胞毒性，以及在人类肿瘤异种移植物中化学疗法的效率。 MDR1反义S-ODN I使多药耐药SW620 Ad300人结肠癌细胞的DOX IC50值在体外降低了9倍，而乳腺癌细胞则降低了7至10倍。 DOX细胞毒性的增加与反义S-ODN I处理的SW620 Ad300细胞中MDR1 mRNA的显着减少有关。即使在反义S-ODN I处理的细胞中，P-gp水平在第三天结束时有所降低，但与mRNA相比，降低的速率仅是部分的。 MDR1反义S-ODN I或II和DOX 4天的组合治疗显着控制了裸鼠体内人类肿瘤的肿瘤生长速率。我们的结果表明，MDR1反义S-ODN治疗可以通过抑制基因表达和耐药表型来提高化疗的效率。

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