Modulation of multidrug resistance gene (mdr-I) with antisense oligodeoxynucleotides

• Published in: Clinical science (1979) Vol. 91; no. 1; pp. 93 - 98
• Main Authors: LIU, C, QURESHI, I. A, DING, X.-J, SHAN, Y.-F, HUANG, Y.-W, XIE, Y, JI, M.-R
• Format: Conference Proceeding Journal Article
• Language: English
• Published: London Portland Press 01.07.1996
• Subjects: ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; Base Sequence; Biological and medical sciences; Cell Division - drug effects; Daunorubicin - pharmacokinetics; Drug Resistance, Multiple - genetics; Drug Resistance, Neoplasm - genetics; Gene Expression Regulation, Leukemic - drug effects; Humans; Leukemia, Experimental - genetics; Leukemia, Experimental - metabolism; Leukemia, Experimental - pathology; Medical sciences; Miscellaneous; Molecular Sequence Data; Oligonucleotides, Antisense - pharmacology; Pharmacology. Drug treatments; Polymerase Chain Reaction; RNA, Messenger - genetics; Tumor Cells, Cultured - drug effects; Antineoplastic agent; Human; Cell culture; Chemotherapy; Oligodeoxyribonucleotide; Gene therapy; Negative therapeutic reaction
• ISSN: 0143-5221; 1470-8736
• DOI: 10.1042/cs0910093

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.