Search results

1

Antisense hairpin loop oligonucleotides as inhibitors of expression of multidrug resistance-associated protein 1: Their stability in fetal calf serum and human plasma.

100%

Rębowski G., Wójcik M., Boczkowska M., Gendaszewska E., Soszyński M., Bartosz G., Niewiarowski W.

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2001

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vol. 48

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issue 4

1061-1076

EN

Multidrug resistance-associated protein (MRP1) is a transmembrane pump protein responsible for the efflux of chemotherapeutic drugs, an important cause of anticancer treatment failure. Trying to circumvent MRP-mediated resistance we designed and synthesized hairpin loops forming antisense oligodeoxyribonucleotides (ODNs), both phosphodiesters (PO-ODNs) and their phosphorothioate analogues (PS-ODNs), to reduce the protein expression by targeting its mRNA in a sequence specific manner. Melting temperature measurements as well as polyacrylamide gel electrophoresis supported the preferential formation of a secondary structure, which was expected to protect ODNs against 3'-exonuclease degradation. ODNs and PS-ODNs designed in this work were successfully tested as antisense inhibitors of the expression of MRP1 in the leukaemia HL60/ADR cell line. Foreseeing the necessity to perform clinical studies with such ODNs we investigated their stability against the 3'-exonuclease activity of fetal calf serum and human plasma. Under the conditions, corresponding to physiological ones, we observed high stability of hairpin loop forming ODNs, especially those containing longer (e.g. 7 base pair) stems. Comparative studies on the stability of chemically unmodified hairpin loop forming ODNs and their PS-counterparts indicated that endonuclease activity did not play any important role in the process of their nucleolytic degradation. Our studies provide strong evidence for high stability of chemically unmodified hairpin loop ODNs, making them an attractive alternative to phosphorothioate analogues commonly used in antisense strategy.

2

Multidrug resistance-associated protein - reduction of expression in human leukaemia cells by antisense phosphorothioate olignucleotides.

100%

Niewiarowski W., Gendaszewska E., Rębowski G., Wójcik M., Mikołajczyk B., Soszyński M., Bartosz G.

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2000

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vol. 47

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issue 4

1183-1188

EN

Multidrug resistance-associated protein (MRP1) causes cellular drug resistance in several cancer cell lines. In this paper we show that antisense oligonucleotides decrease MRP1 expression in human leukaemia cells. We investigated biological activity of a series of 12 linear phosphorothioate oligonucleotides, complementary to several regions of MRP1 mRNA. The oligonucleotides were administered to leukaemia HL60/ADR cells overexpressing MRP1 protein. Then, the level of MRP1 mRNA was determined by means of semiquantitative RT-PCR and the protein level by reaction with specific monoclonal antibodies. Some of the investigated antisense oligonucleotides decrease the expression level of the MRP1 protein by 46% and its mRNA level by 76%.

3

Synthesis, biochemical and biological studies on oligonucleotides bearinga lipophilic dimethoxytrityl group

84%

Misiura K., Wójcik M., Krakowiak A., Koziołkiewicz M., Pawłowska Z., Pluskota E., Cierniewski C. S., Stec W. J.

Acta Biochimica Polonica

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1998

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vol. 45

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issue 1

27-32

4

Inhibition of plasminogen activator inhibitor release in endothelial cell cultures by antisense oligodeoxyribonucleotides with a 5˘-end lipophilic modification

68%

Kobylańska A., Pluskota E., Światkowska M., Wójcik M., Cierniewska-Cieślak A., Krakowiak A., Boczkowska M., Pawłowska Z., Okruszek A., Koziołkiewicz M., Cierniewski C. S., Stec W. J.

Acta Biochimica Polonica

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1999

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vol. 46

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issue 3

679-691

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4 Acta Biochimica Polonica

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4 Wójcik M.

2 Bartosz G.

2 Boczkowska M.

2 Cierniewski C. S.

2 Gendaszewska E.

2 Koziołkiewicz M.

2 Krakowiak A.

2 Niewiarowski W.

2 Pawłowska Z.

2 Pluskota E.

2 Rębowski G.

2 Soszyński M.

2 Stec W. J.

1 Cierniewska-Cieślak A.

1 Kobylańska A.

1 Mikołajczyk B.

1 Misiura K.

1 Okruszek A.

1 Światkowska M.

Antisense hairpin loop oligonucleotides as inhibitors of expression of multidrug resistance-associated protein 1: Their stability in fetal calf serum and human plasma.

Multidrug resistance-associated protein - reduction of expression in human leukaemia cells by antisense phosphorothioate olignucleotides.

Synthesis, biochemical and biological studies on oligonucleotides bearinga lipophilic dimethoxytrityl group

Inhibition of plasminogen activator inhibitor release in endothelial cell cultures by antisense oligodeoxyribonucleotides with a 5˘-end lipophilic modification