Überwindung der P-Glykoprotein (MDR1)-abhängigen Multidrugresistenz mittels RNA-Interferenz Alexandra Eva StegeMeiner Familie1121.11.1.13491#2441.24561.3781.41.4.19510#39710111.4.21.4.2.11.4.2.2121.51.5.113529#4511.5.214495#2921.61516529#55322.12.1.12.1.1.1162.1.1.2172.1.1.3182.1.22.1.3192.1.42.1.52.1.62021411#93222.1.72.1.8232.1.92.22.2.1242.2.22.2.2.125262.2.2.2272.2.2.32.2.2.3.12.2.2.3.22.2.2.428292.2.32.2.3.1302.2.3.22.2.3.32.2.42.2.4.12.2.4.1.1312.2.4.1.232302#27133342.2.4.22.2.4.2.1352.2.4.2.2362.2.52.2.5.12.2.5.22.2.5.32.2.5.3.137382.2.5.3.2392.2.5.4402.2.5.52.2.5.6412.2.5.72.2.5.8422.2.62.2.6.12.2.6.22.2.6.2.1432.2.6.2.2442.2.6.2.3452.2.6.2.4462.2.6.32.2.6.3.12.2.6.3.2472.2.6.3.3482.2.6.42.2.72.2.7.1492.2.7.2502.2.7.32.2.7.3.1512.2.7.3.2522.2.7.3.3532.2.7.454354553.13.1.13.1.23.1.2.156343#74557321#75058321#7143.1.2.25960359#61261531#4953.1.362415#475397#52063397#5023.23.2.164495#33665604#23266434#4723.2.26768415#6293.2.369381#3473.2.470359#400605#58771605#3863.2.572359#47573359#4763.374302#2293.3.175283#3023.3.276396#3793.3.377729#501477784.1794.2804.2.14.2.281824.2.34.2.3.1834.384854.48687GlossarLiteraturverzeichnisDanksagungLebenslaufPublikationenSelbständigkeitserklärungdeInhaltsverzeichnisHilfe Literaturverzeichnis Ambudkar, S.V., Dey, S., Hrycyna, C.A. et al. (1999): Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu. Rev. Pharmacol. Toxicol. 39, 361-398. Ambudkar, S.V., Kimchi-Sarfaty, C., Sauna, Z.E. & Gottesman M.M. (2003): P-glycoprotein: from genomics to mechanism. Oncogene 22, 7468-7485. Arcamone, F., Cassinelli, G., Fantini, G. et al. (1969): Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius. Biotechnol. Bioeng. 11 (6), 1101-1110. Arnal, M., Franco, N., Fargeot, P. et. al. (2000): Enhancement of mdr1 gene expression in normal tissue adjacent to advanced breast cancer. Breast Cancer Res. Treat. 61 (1), 13-20. Aubel-Sadron, G., Londos-Gagliardi, D (1984): Daunorubicin and doxorubicin, anthracycline antibiotics, a physicochemical and biological review.Biochimie 66 (5), 333-352. Baldini, N., Scotlandi, K., Barbanti-Brodano, G. et al. (1995): Expression of P-glycoprotein in high-grade osteosarcomas in relation to clinical outcome. N. Engl. J. Med. 333 (21) , 1380-1385 Bartel, D.P. (2004): MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116 (2), 281-297. Bass, B.L. (2001): RNA interference. The short answer. Nature 411 (6836), 428-429. Benderra, Z., Trussardi, A., Morjani, H. et.al. (2000): Regulation of cellular glutathione modulates nuclear accumulation of daunorubicin in human MCF7 cells overexpressing multidrug resistance associated protein. Eur. J. Cancer 36 (3), 428-434. Borst, P., Evers, R., Kool, M. & Wijnholds, J. (1999): The multidrug resistance protein family. Biochim. Biophys. Acta 1461(2), 347-357. Borst, P. & Elferink, R.O. (2002): Mammalian ABC transporters in health and disease. Annu. Rev. Biochem. 71, 537-592. Booser, D.J., Hortobagyi, G.N. (1994): Anthracycline antibiotics in cancer therapy. Focus on drug resistance. Drugs 47 (2), 223-258. Brangi, M., Litman, T., Ciotti, M. & Nishiyama, K. (1999): Camptothecin resistance: role of the ATP-binding cassette (ABC), mitoxantrone-resistance half-transporter (MXR), and potential for glucuronidation in MXR-expressing cells. Cancer Res. 59 (23), 5938-5946. Bridge, A.J., Pebernard, S., Ducreaux, A. et. al. (2003): Induction of an interferon response by RNAi vectors in mammalian cells. Nat Genet. 34 (3), 263-264. Brummelkamp, T.R., Bernards, R., Agami, R. (2002): A system for stable expression of short interfering RNAs in mammalian cells. Science 296, 550-553, Celius, T., Garberg, P. & Lundgren, B. (2004): Stable suppression of MDR1 gene expression and function by RNAi in Caco-2 cells. Biochemical and Biophysical Research Communications 324, 365-371. Cerutti, L., Mian, N. & Bateman, A. (2000): Domains in gene silencing and cell differentiation proteins: the novel PAZ domain and redefinition of the Piwi domain. Trends Biochem. Sci. 25 (10), 481-482. Chan, H. S., Thorner, P. S., Haddad, G. & Ling, V. (1990): Immunohistochemical detection of P-glycoprotein: prognostic correlation in soft tissue sarcoma of childhood. J. Clin. Oncol. 8 (4), 689-704. Chan, H. S., Haddad, G., Thorner, P.D. et al. (1991): P-glycoprotein expression as a predictor of the outcome of therapy for neuroblastoma. N. Engl. J. Med. 325 (23), 1608-14. Chaudhary, P.M., Roninson, I. B. (1993): Induction of multidrug resistance in human cells by transient exposure to different chemotherapeutic drugs. J. Natl. Cancer Inst. 85 (8), 632-639 Chen, C.J., Chin, J.E., Ueda, K. et al. (1986): Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell 47, 381-389. Cogoni, C. & Macino, G. (1999): Homology-dependent gene silencing in plants and fungi: a number of variations on the same theme.Curr. Opin. Microbiol. 2, 657-662. Cole, S.P., Bhardwaj, G., Gerlach, J.H. et al.(1992): Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258 (5088), 1650-1654. Conrad, C., Rauhut, R. (2002): Ribonuclease III: new sense from nuisance. Int. J. Biochem. Cell Biol. 34 (2), 116-129. Cordon-Cardo, C., O'Brien, J.P. & Posner, J.B. (1989): Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc. Natl. Acad. Sci. USA. 86 (2), 695-698. Dean, M., Hamon, Y., Chinini, G. et al. (2001): The human ATP-binding cassette (ABC) transporter superfamily. J. Lipid Res. 42 (7), 1007-1017. Den Boer, M.L., Pieters, R., Kazemier, K.M. et al. (1999): Relationship between the intracellular daunorubicin concentration, expression of major vault protein/lung resistance protein and resistance to anthracyclines in childhood acute lymphoblastic leukemia. Leukemia 13(12), 2023-2030. Dietel, M., Arps, H., Lage, H. & Niendorf, A. (1990): Membrane vesicle formation due to acquired mitoxantrone resistance in human gastric carcinoma cell line EPG85-257. Cancer Res. 50 (18), 6100-6106. Dold, U., Hermanek, P., Hoffken, K. & Sack, H. (1993): Allgemeine Prinzipien der Tumortherapie. Praktische Tumortherapie. S.49-108, Hrsg.: Dold, U., Hermanek, P., Hoffken, K., Sack, H. Thieme-Verlag. Doyle, L.A., Yang, W., Abruzzo, L.V. et al. (1998): A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc. Natl. Acad. Sci. USA 95 (26), 15665-15670. Duan, Z., Brakora, K.A., Seiden, M.V. (2004): Inhibition of ABCB1 (MDR1) and ABCB4 (MDR3) expression by small interfering RNA and reversal of paclitaxel resistance in human ovarian cancer cells. Mol. Cancer Ther. 3 (7), 833-838. Dubost, M., Ganter, P., Maral, R. et al. (1963): A new antibiotic with cytostatic properties: rubidomycin. C. R. Hebd. Seances. Acad. Sci. 257 : 1813-1815. French. Dykxhoorn, D.M., Novina, C.D. & Sharp, P.A. (2003): Killing the messenger: Short RNAs that silence gene expression. Nature Rev. Mol. Cell Biol. 4, 457-467. Elbashir, S.M., Harborth, J., Weber, K. & Tuschl, T. (2002): Analysis of gene function in somatic mammalian cells using small interfering RNAs. Methods 26 (2), 199-213. Elbashir, S.M., Harborth, J., Lendeckel, W. et al. (2001): Duplexes of 21-nucleotide RNAs mediate RNA interfernce in cultured mammalian cells. Nature 411, 494-498. Ferry, D.R., Smith, A., Malkhandi, J. et al. (1996): Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin. Cancer Res. 2 (4), 659-668. Fire, A., Xu, S., Kostas, S.A. et al. (1998): Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806-811. Fricker, S.P. & Buckley, R.G. (1996): Comparison of two colorimetric assays as cytotoxicity endpoints for an in vitro screen for antitumour agents. Anticancer Res. 16 (6B), 3755-3760. Gadsby, D.C., Csanady, L., Vergani, P. (2006): The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature 440 (7083), 477-483. Gottesman, M.M., Pastan, I. (1993): Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem. 62, 385-427. Gottesman, M.M., Pastan, I. & Ambudkar, S.V. (1996): P-glycoprotein and multidrug resistance. Curr. Opin. Genet. Dev. 6 (5), 610-617. Gottesman, M.M., Fojo, T., Bates, S.E. (2002): Multidrug resistance in cancer: role of ATP-dependent transporters. Nat. Rev. Cancer 2 (1), 48-58. Gottesman, M.M. (2002): Mechanisms of cancer drug resistance. Annu. Rev. Med. 53, 615-627. Grünweller, A., Wyszko, E., Bieber, B. et al.(2003): Comparison of different antisense strategies in mammalian cells using locked nucleic acids, 2'-O-methyl RNA, phosphorothioates and small interfering RNA. Nucleic Acids Res. 31 (12), 3185-3193. Hannon, G.J. (2002): RNA interference. Nature 418 (6894), 244-251. Harborth, J., Elbashir, S.M., Bechert, K. et al. (2001): Identification of essential genes in cultured mammalian cells using small interfering RNAs. J. Cell Sci. 114 (Pt 24), 4557-4565. Higgins, C.F. (1992): ABC transporters: from microorganisms to man. Annu. Rev. Cell Biol. 8, 67-113. Higgins, C.F., Callaghan, R., Linton, K.J. et al. (1997): Structure of the multidrug resistance P-glycoprotein. Semin. Cancer Biol. 8 (3), 135-142. Hipfner, D.R., Deeley, R.G. & Cole, S.P. (1999): Structural, mechanistic and clinical aspects of MRP1. Biochim. Biophys. Acta 1461(2), 359-376. Hoffmeyer, S., Burk, O., von Richter, O. et al. (2000): Functional polymorphisms of the human multidrug-resistance gene. Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc. Natl. Acad. USA 97 , 3473-3478. Holen, T., Amarzguioui, M., Wiiger, M.T. et al. (2002): Positional effects of short interfering RNAs targeting the human coagulation trigger Tissue Factor. Nucleic Acids Res. 30 (8), 1757-1766. Holm, P.S., Scanlon, K.J. & Dietel, M. (1994): Reversion of multidrug resistance in the P-glycoprotein-positive human pancreatic cell line (EPP85-181RDB) by introduction of a hammerhead ribozyme. Br. J. Cancer. 70 (2), 239-243. Holm, P.S., Krupp, G., Dietel, M. (1995): Similar cleavage efficiencies of an oligoribonucleotide substrate and an mdr1 mRNA segment by a hammerhead ribozyme. Gene 167 (1-2), 221-225. Holm, P.S., Lage, H., Bergmann, S. et al. (2004): Multidrug-resistant cancer cells facilitate E1-independent adenoviral replication: impact for cancer gene therapy. Cancer Res. 64 (1), 322-328. Jacque, J.-M., Triques, K. & Stevenson, M. (2002): Modulation of HIV1-replication by RNA interference. Nature 418, 435-438. Jagus, R., Joshi, B. & Barber, G.N. (1999): PKR, apoptosis and cancer. Int. J. Biochem Cell Biol. 31 (1), 123-138. Jin, S., Scotto, K.W. (1998): Transcriptional regulation of the MDR1 gene by histone acetyltransferase and deacetylase is mediated by NF-Y. Mol. Cell Biol. 18 (7), 4377-4384. Johnson, D.R., Finch, R.A., Lin, Z.P. et al.(2001): The pharmacological phenotype of combined multidrug-resistance mdr1a/1b- and mrp1-deficient mice. Cancer Res. 61 (4), 1469-1476. Juliano, R.L., Ling, V.. (1976): A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochem. Biophys. Acta. 455, 152-162. Kartner, N., Riordan, J.R. & Ling, V. (1983): Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science 221 (4617), 1285-1288. Kaszubiak, A., Holm, P.S. & Lage, H. (eingereicht): Reversal of the classical multidrug resistance (MDR) phenotype by adenoviral delivery of anti-MDR1 short hairpin RNAs and ribozymes. Kawasaki, H., Taira, K. (2004): Induction of DNA methylation and gene silencing by short interfering RNAs in human cells. Letters to Nature 431, 211-216. Kawasaki, H. & Taira, K. (2003): Short hairpin type of dsRNAs that are controlled by tRNA(Val) promoter significantly induce RNAi-mediated gene silencing in the cytoplasm of human cells. Nucleic. Acids Res. 31, 700-707. Kioka, N., Yamano, Y., Komano, T. et al. (1992): Heat-shock responsive elements in the induction of the multidrug resistance gene (MDR1). FEBS Lett . 301 (1), 37-40. Klimecki, W.T., Futscher, B.W., Grogan, T.M. & Dalton, W.S. (1994): P-glycoprotein expression and function in circulating blood cells from normal volunteers. Blood 83 (9), 2451-2458. Kobayashi, H., Dorai, T., Holland, J.F. & Ohnuma, T. (1994): Reversal of drug sensitivity in multidrug-resistant tumor cells by an MDR1 (PGY1) ribozyme. Cancer Res. 54 (5), 1271-1275. Kowalski, P., Stein, U., Scheffer, G.L. & Lage, H. (2002): Modulation of the atypical multidrug-resistant phenotype by a hammerhead ribozyme directed against the ABC transporter BCRP/MXR/ABCG2. Cancer Gene Ther. 9 (7), 579-586. Kowalski, P., Surowiak, P., Lage, H. (2005): Reversal of different drug-resistant phenotypes by an autocatalytic multitarget multiribozyme directed against the transcripts of the ABC transporters MDR1/P-gp, MRP2, and BCRP. Mol Ther. 11 (4), 508-522. Krishna, R. & Mayer, L.D. (2000): Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. European J. of Pharmaceutical Sciences 11, 265-283. Labialle, S., Gayet, L., Marthinet, E. et al. (2002): Transcriptional regulators of the human multidrug resistance 1 gene: recent views. Biochem. Pharmacol. 64 (5-6), 943-948. Labialle, S., Dayan, G., Michaud, M. et al.(2005): Gene therapy of the typical multidrug resistance phenotyp of cancer: a new hope? Semin. Oncol. 32 (6), 583-590. Lage, H., Jordan, A., Scholz, R. & Dietel, M. (2000): Thermosensitivity of multidrug-resistant human gastric and pancreatic carcinoma cells. Int. J. Hyperthermia 16 (4), 291-303. Lage, H., Dietel, M. (2002): Multiple mechanisms confer different drug-resistant phenotypes in pancreatic carcinoma cells. J. Cancer Res. Clin. Oncol. 128 (7), 349-357. Lage, H. (2006): MDR1/P-glycoprotein (ABCB1) as target for RNA Interference-mediated reversal of multidrug resistance. Current Drug Targets 7 (7), 813-21. Lee, N.S., Dohjima, T., Bauer, G. et. al. (2002): Expression of small interfering RNAs targeted against HIV-1 rev transcripts in human cells. Nat. Biotechnol. 20 (5), 500-505. Leith, C.P., Kopecky, K.J., Chen, I.M. et. al. (1999): Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study. Blood 94 (3), 1086-99. Lewis, D.L., Hagstrom, J.E., Loomis, A.G. et. al. (2002): Efficient delivery of siRNA for inhibition of gene expression in postnatal mice. Nat Genet. 32 (1), 107-108. Lippmann, Z. & Martienssen, R. (2004). The role of RNA interference in heterochromatic silencing. Nature 431, 364-370. Ling, Y.H., Priebe, W., Yang, L.Y. et al. (1993): In vitro cytotoxicity, cellular pharmacology, and DNA lesions induced by annamycin, an anthracycline derivative with high affinity for lipid membranes. Cancer Res. 53 (7), 1583-1589. Litman, T., Brangi, M., Hudson, E. et al. (2000): The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2). J. Cell Sci. 113, 2011-2021. Liu, C., Qureshi, I.A., Ding, X. et al. (1996): Modulation of multidrug resistance gene (mdr-1) with antisense oligodeoxynucleotides. Clin. Sci. (Lond). 91 (1), 93-98. Loe, D.W., Almquist, K.C., Deeley, R.G. & Cole, S.P. (1996): Multidrug resistance protein (MRP)-mediated transport of leukotriene C4 and chemotherapeutic agents in membrane vesicles. Demonstration of glutathione-dependent vincristine transport. J. Biol. Chem. 271 (16), 9675-9682. Lum, B.L. & Gosland, M.P. (1995): MDR expression in normal tissues. Pharmacologic implications for the clinical use of P-glycoprotein inhibitors. Hematol. Oncol. Clin. North Am. 9 (2), 319-336. Materna, V., Stege, A., Surowiak, P., et al. (in Druck; 2006): RNA interference-triggered reversal of ABCC2-dependent cisplatin resistance in human cancer cells. Biochemical and Biophysical Research Communications Matsui, Y., Kobayashi, N., Nishikowa, M. & Takakura, Y. (2005): Sequenz-specific suppression of mdr1a/1b express i on in mice via RNA interference. Pharm. Res. 22 (12), 2091-2098. Matzke, M.A. & Birchler, J.A. (2005): RNAi-mediated pathways in the nucleus. Nat. Rev. Genet. 6 (1), 24-35. McCaffrey, A.P., Meuse, L., Pham, T.T. et. al. (2002): RNA interference in adult mice. Nature 418 (6893) , 38-39. Miyagishi, M., Taira, K. (2002): Development and application of siRNA expression vector. Nucleic Acids Res. Suppl. (2), 113-114. Miyagishi, M., Hayashi, M., Taira, K. (2003): Comparison of the suppressive effects of antisense oligonucleotides and siRNAs directed against the same targets in mammalian cells. Antisense Nucleic Acid Drug Dev. 13 (1), 1-7. Miyake, K., Mickley, L., Litman, T. et al. (1999): Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes. Cancer Res. 59 (1), 8-13. Montgomery, M.K., Xu, S. & Fire, A. (1998): RNA as a target of double-stranded RNA-mediated genetic interference in Caenorhabditis elegans . Proc. Natl. Acad. Sci. USA 95, 15502-15507. Muratovska, A., Eccles, M.R. (2004): Conjugate for efficient delivery of short interfering RNA (siRNA) into mammalian cells. FEBS Lett. 558 (1-3), 63-68. Napoli, C., Lemieux, C., Jorgensen, R. (1990): Introduction of a Chimeric Chalcone Synthase Gene into Petunia Results in Reversible Co-Suppression of Homologous Genes in trans. Plant Cell. 2 (4), 279-289. Nieth, C. & Lage, H. (2005): Induction of the ABC-transporters MDR1/P-gp (ABCB1), MRPl (ABCC1), and BCRP (ABCG2) during establishment of multidrug resistance following exposure to mitoxantrone. J. Chemother. 17 (2), 215-223. Nieth, C., Priebsch, A., Stege, A. & Lage, H. (2003): Modulation of the classical multidrug resistance (MDR) phenotyp by RNA interference (RNAi). FEBS Letters 545, 144-150. Pastan, I. & Gottesman, M.M. (1987): Multiple-drug resistance in human cancer. N. Engl. J. Med. 316 (22), 1388-1393. Paul, C.P., Good, P.D., Winer, I. & Engelke, D.R. (2002): Effective expression of small interfering RNA in human cells. Nat. Biotechnol. 20 (5), 505-508. Perez, R.P., Godwin, A.K., Handel, L.M. & Hamilton, T.C. (1993): A comparison of clonogenic, microtetrazolium and sulforhodamine B assays for determination of cisplatin cytotoxicity in human ovarian carcinoma cell lines. Eur. J. Cancer 9A (3), 395-399. Pfreundschuh, M. Prinzipien der medikamentösen Tumorpathologie. Kompendium Internistische Onkologie. S.357-412, Hrsg.: Schmoll, H. J., Höffken, K. & Possinger, K. (1996] 2. Auflage Springer-Verlag. Pichler, A., Zelcer, N., Prior, J.L. et al. (2005): In vivo RNA interference-mediated ablation of MDR1 P-glycoprotein. Cancer Therapy: Preclinical. 11, 4487-4494. Pirker, R., Wallner, J., Geissler, K. et al. (1991): MDR1 gene expression and treatment outcome in acute myeloid leukemia.. J. Natl. Cancer Inst. 83 (10), 708-712. Pratt, W.B., Ruddon, R.W., Ensminger, W.D. & Magbaum J. (1994): The anticancer drugs. Oxford Univ Press. Priebsch, A., Rompe, F., Kowalski, P., et al. (akzeptiert; 2006): Complete reversal of ABCG2-depending atypical multidrug resistance (MDR) by RNA interference in human gastric carcinoma cells. Oligonucleotides Read, M.L., Stevenson, M., Farrow, P.J. et al. (2003): RNA-based therapeutic strategies for cancer. Exp. Opin. Ther. Patents 13, 627-638. Reynolds, A., Leake, D., Boese, Q. et al. (2004): Rational siRNA design for RNA interference. Nat. Biotechnol. 22 (3) , 326-330. Riordan, J.R., Deuchars, K., Kartner, N. et al. (1985): Amplification of P-glycoprotein genes in multidrug-resistant mammalian cell lines. Nature 316 (6031), 817-819. Rittierodt, M., Tschernig, T., Harada, K. (2004): Modulation of multidrug-resistance-associated P-glycoprotein in human U-87 MG and HUV-ECC cells with antisense oligodeoxynucleotides to MDR1 mRNA. Pathobiology 71 (3), 123-128. Robert Koch Institut (2006) http://www.rki.de/cln_011/nn_226978/DE/Content/GBE/DachdokKrebs/Broschuere/kid2006,templateId=raw,property=publicationFile.pdf/kid2006 Rocchi, E., Khodjakov, A., Volk, E.L. et al. (2000): The product of the ABC half-transporter gene ABCG2 (BCRP/MXR/ABCP) is expressed in the plasma membrane. Biochem. Biophys. Res. Commun. 271 (1), 42-46 Rubinson, D.A., Dillon, C.P., Kwiatkowski A.V. et al. (2003): A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nat. Genet. 33 (3), 401-406. Rye, P.D. & Sti g brand, T. (2004): Interfering with cancer: A brief ou t line of advances in RNA interference in oncology. Tumo r Biology 25, 329-336. Sanger, F., Nicklen, S., Coulson, A.R. (1977): DNA sequencing with chain-terminating inhibitors. Proc. Natl. Acad. Sci. USA 74 (12), 5463-5467. Saurin, W., Hofnung, M. & Dassa, E. (1999): Getting in or out: early segregation between importers and exporters in the evolution of ATP-binding cassette (ABC) transporters. J. Mol. Evol. 48 (1), 22-41. Scherr, M., Morgan, M.A. & Eder, M. (2003): Gene silencing mediated by small interfering RNAs in mammalian cells. Curr. Med. Chem. 10 (3), 245-256. Schi n kel, A.H. (1997): The physiology function of drug-transporting P-glycoproteins. Sem. Cancer Biol. 8, 161-170. Schneider, E. & Hunke, S. (1998): ATP-binding-cassette (ABC) transport systems: functional and structural aspects of the ATP-hydrolyzing subunits/domains. FEMS Microbiol. Rev. 22 (1), 1-20. Schwarz, D.S., Hutvagner, G., Du, T., Xu, Z., Aronin, N. & Zamore, P.D. (2003): Asymmetry in the assembly of the RNAi enzyme complex. Cell 115 (2), 199-208. Shen, D.W., Fojo, A., Roninson, I.B. et al. (1986): Multidrug resistance of DNA-mediated transformants is linked to transfer of the human mdr1 gene. Mol. Cell Biol. 6 (11), 4039-45 Shen, D.W., Pastan, I. & Gottesmann, M.M. (1998): Cross-resistance to methotrexate and metals in human cisplatin-resistant cell lines results from a pleiotropic defect in accumulation of these compounds associated with reduced plasma membrane binding proteins. Cancer Res. 58, 258-275. Siolas, D., Lerner, C., Burchard, J. et al. (2005): Synthetic shRNAs as potent RNAi triggers. Nat. Biotechnol. 23 (2), 227-231. Skehan, P., Storeng, R., Scudiero, D. et al. (1990): New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst. 82 (13), 1107-1112. Sledz, C.A., Holko, M., de Veer, M.J. et al. (2003): Activation of the interferon system by short-interfering RNAs. Nature Cell Bi o logy 5, 834-839. Stark, G.R., Kerr, I.M., Williams, B.R. et al. (1998): How cells respond to interferons. Annu. Rev. Biochem. 67, 227-264. Stege, A., Priebsch, A., Nieth, C. & Lage, H. (2004): Stable and complete overcoming of MDR1/P-glycoprotein-mediated multidrug resistance in human gastric carcinoma cells by RNA interference. Cancer Gene Ther. 11 (11), 699-706. Stein, U., Walther, W., Lemm, M. et al. (1997): Development and characterisation of novel human multirug resistant mammary carcinoma lines in vitro and in vivo. Int. J. Cancer. 72, 885-891. Stein, U., Jürchott, K., Schläfke, M. et al. (2002): Expression of multidrug resistance genes MVP, MDR1, and MRP1 dtermined sequentially before, during, and after hyperthermic isolated limb perfusion of soft tissue sarcoma and melanoma patients. J. Clin. Oncol. 20, 3282-3292. Stein, U., Stege, A., Surowiak, P., Walther, W. & Lage, H. (eingereicht): Complete in vivo reversal of the multidrug resistance (MDR) phenotype in a breast cancer model by jet-injection of anti-MDR1 short hairpin RNA-encoding plasmid DNA. Molecular Cancer Therapeutics Stuart, D.D., Kao, G.Y. & Allen, T.M. (2000): A novel, long-circulating, and functional liposomal formulation of antisense oligodeoxynucleotides targeted against MDR1. Cancer Gene Ther. 7 (3), 466-475. Thiebaut, F., Tsuruo, T., Hamada, H. et al.(1987): Cellular localization of the multidrug resistance gene product P-glycoprotein in normal human tissues. Proc. Natl. Acad. Sci. USA 84, 7735-7738. Tritton TR. (1991): Cell surface actions of adriamycin. Pharmacol. Ther. 49 (3), 293-309. Trock, B.J., Leonessa, F., Clarke, R. (1997): Multidrug resistance in breast cancer: a meta-analysis of MDR1/gp170 expression and ist possible functional significance. J. Natl. Cancer Inst. 89 (13), 917-931. Tuschl, T. (2002): Expanding small RNA interference. Nat. Biotechnol. 20 (5), 446-448. Ueda, K., Cardarelli, C., Gottesman, M.M. & Pastan, I. (1987): Expressing of a full-length cDNA for the human MDR1 gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc. Natl. Acad. Sci. USA 84, 3004-3008. Vasanthakumar, G., Ahmed, N.K. (1989): Modulation of drug resistance in a daunorubicin resistant subline with oligonucleoside methylphosphonates. Cancer Commun. 1 (4), 225-232. Vermeulen, A., Behlen, L., Reynolds, A. (2005): The contributions of dsRNA structure to Dicer specificity and efficiency. RNA 11 (5), 674-682. Vickers, T.A., Koo, S., Bennett, C.F. et. al. (2003): Efficient reduction of target RNAs by small interfering RNA and RNase H-dependent antisense agents. A comparative analysis. J Biol Chem. 278 (9), 7108-7118. Voigt, W. (2005): Sulforhodamine B assay and chemosensitivity. Methods Mol Med. 110, 39-48. Wagener, C. (1996): Molekulare Onkologie. Hrsg.: Wagener, C. Thieme-Verlag. Walther, W., Stein, U., Fichtner, I. et al. (2002): Intratumoral low-volume jet-injection for efficient nonviral gene transfer. Mol. Biotechnol. 21 (2), 105-115. Warneck, V. & Vornlocher, H.-P. (2003): siRNA als Plattform für die Entwicklung innovativer Therapeutika in der Onkologie. Onkologe 9 , 1121-1129 . Waterhouse, P.M., Graham, M.W. & Wang, M.B. (1998): Virus resistance and gene silencing in plants can be induced by simultaneous expression of sense and antisense RNA. Proc. Natl. Acad. Sci. USA 95 (23), 13959-13964. Widmaier, R., Wildner, G.P., Papsdorf, G. & Graffi, I. (1974): Über eine neue, in vitro unbegrenzt wachsende Zellinie MaTu von Mamma-Tumorzellen des Menschen. Arch. Geschwulstforsch. 44 (1), 1-10. Wu, H., Hait, W. N. & Yang, J. M. (2003): Small interfering RNA-induced suppression of MDR1 (P-glycoprotein) restores sensitivity to multidrug-resistant cancer cells. Cancer Res. 63 (7), 1515-1519. Xu, D., Kang, H., Fisher, M & Juliano, R.L. (2004): Strategies for inhibition of MDR1 gene expression. Mol. Pharmacol. 66 (2), 268-275. Yagüe, E., Higgins, C. F. & Raguz, S. (2004): Complete reversal of multidrug res i stance by stable expression of small interfering RNAs targeting MDR1. Gene Therapy 11 (14),1170-1174. Zamore, P. D., Tuschl, T., Sharp, P.A. & Bartel, D.P. (2000): RNAi: Double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell 101, 25-33. Zhou, D. C., Marie, J. P., Suberville, A.M., Zittoun, R. (1992): Relevance of mdr1 gene expression in acute myeloid leukemia and comparison of different diagnostic methods. Leukemia 6 (9), 879-885.