Overcoming multidrug resistance in human tumor cells using free and liposomally encapsulated antisense oligodeoxynucleotides.
Antisense oligonucleotides offer a molecular targeting tool for overcoming cellular multidrug resistance. In order to improve the in vitro and the in vivo transport of oligodeoxynucleotides, we developed a new liposomal delivery system, using the minimal volume entrapment (MVE) technique. We have demonstrated that cellular uptake and intracellular release of oligodeoxynucleotides were facilitated by delivery in liposomes. 15 mers cap phosphorothioate oligodeoxynucleotides complementary to the 5' end of the coding region or to a loop-forming site in the mdr-1 mRNA were encapsulated in liposomes by the MVE method. P-glycoprotein synthesis and doxorubicin resistance were greatly reduced by exposure of the multidrug resistant SKVLB cells to 5 microM liposomally encapsulated oligonucleotide. A lower effect was observed when free oligodeoxynucleotides were used. Oligomers antisense to the loop-forming site appeared to be more effective and more specific in modulating multidrug resistance than oligomers with antisense sequence to the 5' end coding region.
Thierry
A R
AR
Department of Radiation Medicine, Vincent T. Lombardi Cancer Research Center, Georgetown University Medical Center, Washington, D.C. 20007.
Rahman
A
A
Dritschilo
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001483:Base Sequence; D004351:Drug Resistance; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D008081:Liposomes; D008562:Membrane Glycoproteins / Q000235:genetics*; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008081:Liposomes; D008562:Membrane Glycoproteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger