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Molecular Pharmacology

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Research ArticleArticle

ATP-Dependent Efflux of CPT-11 and SN-38 by the Multidrug Resistance Protein (MRP) and Its Inhibition by PAK-104P

Zhe-Sheng Chen, Tatsuhiko Furukawa, Tomoyuki Sumizawa, Kenji Ono, Kazumitsu Ueda, Kiyotomo Seto and Shin-Ichi Akiyama
Molecular Pharmacology May 1999, 55 (5) 921-928;
Zhe-Sheng Chen
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Tatsuhiko Furukawa
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Tomoyuki Sumizawa
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Kenji Ono
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Kazumitsu Ueda
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Kiyotomo Seto
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Shin-Ichi Akiyama
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Abstract

Non-P-glycoprotein-mediated multidrug-resistant C-A120 cells that overexpressed multidrug resistance protein (MRP) were 10.8- and 29.6-fold more resistant to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and SN-38, respectively, than parental KB-3-1 cells. To see whether MRP is involved in CPT-11 and SN-38 resistance,MRP cDNA was transfected into KB-3-1 cells. The transfectant, KB/MRP, which overexpressed MRP, was resistant to both CPT-11 and SN-38. 2-[4-Diphenylmethyl)-1-piperazinyl]ethyl-5-(trans-4,6-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate P-oxide (PAK-104P) and MK571, which reversed drug resistance in MRP overexpressing multidrug-resistant cells, significantly increased the sensitivity of C-A120 and KB/MRP cells, but not of KB-3-1 cells, to CPT-11 and SN-38. The accumulation of both CPT-11 and SN-38 in C-A120 and KB/MRP cells was lower than that in KB-3-1 cells. The treatment with 10 μM PAK-104P increased the accumulation of CPT-11 and SN-38 in C-A120 and KB/MRP cells to a level similar to that found in KB-3-1 cells. The ATP-dependent efflux of CPT-11 and SN-38 from C-A120 and KB/MRP cells was inhibited by PAK-104P. DNA topoisomerase I expression, activity, and sensitivity to SN-38 were similar in the three cell lines. Furthermore, the conversion of CPT-11 to SN-38 in KB-3-1 and C-A120 cell lines was similar. These findings suggest that MRP transports CPT-11 and SN-38 and is involved in resistance to CPT-11 and SN-38 and that PAK-104P reverses the resistance to CPT-11 and SN-38 in tumors that overexpress MRP.

Footnotes

  • Send reprint requests to: Dr. Shin-Ichi Akiyama, Department of Cancer Chemotherapy, Institute for Cancer Research, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890, Japan. E-mail:akiyamas{at}khosp2.kufm.kagoshima-u.ac.jp

  • This work was supported by grants from the Ministry of Education, Science and Culture; the Ministry of Health and Welfare, Japan; and the Japan Society for the Promotion of Science.

  • Abbreviations:
    CPT
    camptothecin
    CPT-11
    7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin
    SN-38
    7-ethyl-10-hydroxy camptothecin
    SN38-G
    SN-38 glucuronide
    topo
    DNA topoisomerase
    ADM
    adriamycin
    VCR
    vincristine
    MRP
    multidrug resistance protein
    MDR
    multidrug resistance
    cMOAT
    canalicular multispecific organic anion transporter
    P-gp
    P-glycoprotein
    LTC4
    leukotriene C4
    BSO
    buthionine sulfoximine
    MEM
    minimal essential medium
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    GST
    glutathione S-transferase
    • Received December 2, 1998.
    • Accepted February 22, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (5)
Molecular Pharmacology
Vol. 55, Issue 5
1 May 1999
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Research ArticleArticle

ATP-Dependent Efflux of CPT-11 and SN-38 by the Multidrug Resistance Protein (MRP) and Its Inhibition by PAK-104P

Zhe-Sheng Chen, Tatsuhiko Furukawa, Tomoyuki Sumizawa, Kenji Ono, Kazumitsu Ueda, Kiyotomo Seto and Shin-Ichi Akiyama
Molecular Pharmacology May 1, 1999, 55 (5) 921-928;

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Research ArticleArticle

ATP-Dependent Efflux of CPT-11 and SN-38 by the Multidrug Resistance Protein (MRP) and Its Inhibition by PAK-104P

Zhe-Sheng Chen, Tatsuhiko Furukawa, Tomoyuki Sumizawa, Kenji Ono, Kazumitsu Ueda, Kiyotomo Seto and Shin-Ichi Akiyama
Molecular Pharmacology May 1, 1999, 55 (5) 921-928;
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