TY - JOUR
T1 - Reversal of drug sensitivity in MDR subline of P388 leukemia by gene‐targeted antisense oligonucleotide
AU - Nakashima, Emi
AU - Matsushita, Ryo
AU - Negishi, Hiroshi
AU - Nomura, Masaaki
AU - Harada, Shin‐Ichi ‐I
AU - Yamamoto, Hiroshi
AU - Miyamoto, Ken‐Ichi ‐I
AU - Ichimura, Fujio
N1 - Funding Information:
We are grateful to Dr. Motohiro Tanaka for his helpful discussion. P388/S and P388/ADR cells were kindly supplied by Professor Takashi Tsuruo. We also acknowledge the help of Miss Miwako Kuki for her skillful technical assistance. This work was funded in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan.
PY - 1995/10
Y1 - 1995/10
N2 - 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.
AB - 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.
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U2 - 10.1002/jps.2600841012
DO - 10.1002/jps.2600841012
M3 - Article
C2 - 8801335
AN - SCOPUS:0029144340
SN - 0022-3549
VL - 84
SP - 1205
EP - 1209
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 10
ER -