Abstract
Small interfering RNAs (siRNAs) are potentially powerful tools for therapeutic gene regulation. DNA cassettes encoding RNA polymerase III promoter-driven hairpin siRNAs allow long-term expression of siRNA in targeted cells. A variety of viral vectors have been used to deliver such cassettes to cells. Here we report on the development and use of a self-complementary recombinant adeno-associated virus (scAAV) vector for siRNA delivery into mammalian cells. We demonstrate that this modified vector efficiently delivers siRNA into multidrug-resistant human breast and oral cancer cells and suppresses MDR1 gene expression. This results in rapid, profound, and durable reduction in the expression of the P-glycoprotein multidrug transporter and a substantial reversion of the drug-resistant phenotype. This research suggests that scAAV-based vectors can be very effective agents for efficient delivery of therapeutic siRNA.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Antibiotics, Antineoplastic / therapeutic use
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics
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Breast Neoplasms / therapy*
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Cell Proliferation
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Combined Modality Therapy
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Dependovirus / genetics*
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Down-Regulation
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Doxorubicin / therapeutic use
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Drug Resistance, Neoplasm*
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Gene Expression / drug effects
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Genetic Vectors*
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Humans
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Mouth Neoplasms / drug therapy
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Mouth Neoplasms / genetics
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Mouth Neoplasms / therapy*
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Nucleic Acid Conformation
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RNA Interference*
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RNA, Messenger / drug effects
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RNA, Small Interfering / genetics*
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Tumor Cells, Cultured
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antibiotics, Antineoplastic
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RNA, Messenger
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RNA, Small Interfering
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Doxorubicin