Antisense oligonucleotide modulation of MDR P-glycoprotein gene expression
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United States of America Patent
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Dec 14, 1999
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Sep 30, 1997
filing date -
Oct 4, 1996
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Abstract
Oligonucleotides are provided which are specifically hybridizable with nucleic acids encoding the human MDR1 P-glycoprotein. Also disclosed are methods of using the oligonucleotides of the invention in methods of modulating the expression of MDR genes, inhibition of which leads to inhibition of the synthesis of MDR P-glycoproteins and thereby inhibits cellular multidrug resistance. Such inhibition is desirable for treating various hyperproliferative disorders or diseases, such as various cancers, in conjunction with chemotherapy utilizing one or more chemotherapeutic agents, for preventing or modulating the development of multidrug resistance during the chemotherapeutic treatment of an animal, and for resensitizing hyperproliferative MDR cells in an animal having such diseases or disorders that has been previously exposed to chemotherapeutic agents. Modified derivatives of the oligonucleotides of the invention, such as chimeras and conjugates (e.g., of an oligonucleotide and a lipophilic moiety, such as cholesterol), are also disclosed. The biological activity and cellular uptake of oligonucleotides is enhanced by such modifications.
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