Modulation of multidrug resistance gene (mdr-1) with antisense oligodeoxynucleotides.
Modulation of multidrug resistance gene (mdr-1) with antisense oligodeoxynucleotides.
复制标题
DOI：
10.1042/cs0910093
复制
发表时间：
1996-07
期刊：
影响因子：
6
通讯作者：
Chao Liu;I. A. Qureshi;Xun-Jie Ding;Yi-Fei Shan;Y. Huang;Yi Xie;Mei-Rong Ji
中科院分区：
文献类型：
--
作者：
Chao Liu;I. A. Qureshi;Xun-Jie Ding;Yi-Fei Shan;Y. Huang;Yi Xie;Mei-Rong Ji
1.多药耐药是肿瘤化疗成功的主要障碍。因此，规避多药耐药性是临床抗癌治疗的重中之重。在许多逆转策略中，反义寡核苷酸可能为克服细胞多药耐药提供一种分子靶向工具。2.合成了MDR-1基因启动子密码子5‘端和第一个ATG密码子起始区991-1007位环形成部位互补的两个17-聚硫代反义寡聚体。目的是研究它们对P-糖蛋白和mdr-1基因功能和表达的影响。3.结果表明，10个Mumol/L反义寡聚物能显著抑制阿霉素诱导的多药耐药K562/Adm细胞的生长。而对亲代(敏感)的K562/S细胞则无此作用。低聚物处理K562/Adm细胞48h后，细胞内柔红霉素积聚明显增加，P-糖蛋白合成明显减少。4.通过逆转录聚合酶链式反应进一步研究[α-32P]dCTP掺入情况，发现反义寡聚体可能通过抑制MDR-1基因转录而导致MDR-1基因表达水平下降。5.反义寡聚物对MDR-1基因表达的高逆转效率和特异性提示其在耐药肿瘤的基因治疗中具有潜在的临床应用价值。
1. Multidrug resistance is the major obstacle to successful cancer chemotherapy. Circumventing multidrug resistance therefore represents a high priority for clinical anti-cancer treatment. Among many reversal strategies, antisense oligodeoxynucleotides may offer a molecular targeting tool for overcoming cellular multidrug resistance. 2. Two 17-mer phosphorothioate antisense oligomers, complementary to the 5' end of the ATG initiator codon-containing region and loop-forming site (located at nucleotides 991-1007 from the first ATG codon) in mdr-1 cDNA sequence, were synthesized. The purpose was to study their effects on the function and expression of P-glycoprotein and mdr-1 gene. 3. The results showed that 10 mumol/l antisense oligomers could significantly inhibit the growth of multidrug resistant K562/Adm cells cultured in adriamycin-containing medium. No such effect was observed for parental (sensitive) K562/S cells. Intracellular daunorubicin accumulation increased greatly in the K562/Adm cells after they were treated with oligomers for 48 h and P-glycoprotein synthesis was strikingly reduced. 4. Further investigation with [alpha-32P]dCTP incorporation by the reverse transcriptase-polymerase chain reaction method revealed that antisense oligomers could result in a reduction in the level of mdr-1 mRNA, probably through hindering mdr-1 gene transcription. 5. The high reversal efficiency and specificity of antisense oligomers in regulating mdr-1 gene expression suggest a potential clinical application in gene therapy for drug resistant malignancies.