Reversal of drug sensitivity in MDR subline of P388 leukemia by gene‐targeted antisense oligonucleotide

Emi Nakashima, Ryo Matsushita, Hiroshi Negishi, Masaaki Nomura, Shin‐Ichi ‐I Harada, Hiroshi Yamamoto, Ken‐Ichi ‐I Miyamoto, Fujio Ichimura

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Abstract

We attempted to reverse multidrug resistance (MDR) by treatment with 25‐mer antisense phosphorothioate oligonucleotide. The phosphorothioate analogs, the sequences of which are sense or antisense to the initiation codon of mouse mdr1 mRNA, were tested against murine leukemic P388/S and adriamycin‐resistant P388/ADR cell lines. A weak inhibitory effect on the growth of P388/S and P388/ADR cells was observed at a sense and antisense oligonucleotide concentration of 30 μM. Using the monoclonal antibody to P‐glycoprotein and a flow cytometry technique, we showed that the level of expression of P‐glycoprotein in P388/ADR cells treated with antisense oligonucleotide was lower than when treated with sense oligonucleotide. The antisense oligonucleotide potentiated the growth‐inhibitory effect of vinblastine on P388/ADR cells, whereas sense oligonucleotide did not. This was accompanied by an increase in vinblastine retention in the cells. The reversal of the resistance by antisense oligonucleotide was increased by the combination with 1 μM verapamil. These results suggest that the antisense oligonucleotide and low dose verapamil may be useful in circumventing the resistance to anticancer drugs of MDR tumors.

Original languageEnglish
Pages (from-to)1205-1209
Number of pages5
JournalJournal of Pharmaceutical Sciences
Volume84
Issue number10
DOIs
Publication statusPublished - 1995 Oct

ASJC Scopus subject areas

  • Pharmaceutical Science

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    Nakashima, E., Matsushita, R., Negishi, H., Nomura, M., Harada, SI. I., Yamamoto, H., Miyamoto, KI. I., & Ichimura, F. (1995). Reversal of drug sensitivity in MDR subline of P388 leukemia by gene‐targeted antisense oligonucleotide. Journal of Pharmaceutical Sciences, 84(10), 1205-1209. https://doi.org/10.1002/jps.2600841012