| Research backgroudResistance to antineoplastic drugs is the major reason why chemotherapy-based treatment modalities of malignant tumors may fail. Multidrug resistance (MDR) means malignant cells are cross resistance to many other structurally and functionally unrelated anticancer drugs once they are resistant to a single anticancer drug.Many kinds of mechanisms contribute to MDR, however, the underlying mechanism conferring this MDR phenotype is the cellular overproduction of the mdr-1 gene-encoded 170-kD, membrane-spanning P-glycoprotein (P-gp, P-170, PGY1, mdr-1, ABCB1), a member of the superfamily of ABC (ATP binding cassette) transporters.Pharmacologically active compounds, designated MDR modulators or chemosensitizers, may circumvent the classical MDR phenotype by inhibiting the efflux pump activity of P-gp. One obstacle in applying MDR modulators arises from their commonly occurring intrinsic toxicity at doses necessary to be active, e.g. heart failure, hypotension, hyperbilirubinemia, and immunosuppression by cyclosporin A. Additionally, tumor cells can develop resistance against the applied chemosensitizers, so-called tertiary resistance. Consequently, it is necessary to develop alternative, less toxic and more efficient strategies to overcome MDR.In previous studies, antisense oligonucleotides were shown to modulate P-gp-dependent MDR. Moreover, hammerhead ribozymes were designed and successfully applied to decrease the expression level of the P-gp-encoding mdr-1 mRNA. Recent years, for its high efficiency, specificity and stablility, RNA interference (RNAi) have become a powerful tool to knock down specific gene expression. RNAi is a post-transcriptional process triggered by the introduction of double-stranded RNA (dsRNA), which leads to gene silencing in a sequence-specific manner. Now, RNAi has been reported to naturally occur in organisms as diverse as plants, fungi, insects, batrachia, aves, nematodes, Drosophila, rat, mice, human and almost all eukaryotic cells.
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