Skip to main content
SpringerLink
Log in

Reversal of multidrug resistance by a novel quinoline derivative, MS-209

  • Original Article
  • MS-209, Quinoline, Multidrug Resistance
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

MS-209, a novel quinoline derivative, was examined for its reversing effect on multidrug-resistant tumor cells. MS-209 at 1–10 μM completely reversed resistance against vincristine (VCR) in vitro in multidrug-resistant variants of mouse leukemia P388 cells (VCR-resistant P388/VCR and Adriamycin (ADM)-resistant P388/ADM) and human leukemia K562 cells (VCR-resistant K562/VCR and ADM-resistant K562/ADM). MS-209 at 1–10 μM also completely reversed resistance against ADM in vitro in P388/VCR cells, K562/VCR cells, and K562/ADM cells. In ADM-resistant P388 (P388/ADM) cells, however, ADM resistance was only partially reversed at the MS-209 concentrations tested. MS-209 enhanced the chemotherapeutic effect of VCR in P388/VCR-bearing mice. When MS-209 was given p.o. at 80 mg/kg twice a day (total dose, 160 mg/kg per day) with 100 μg/kg VCR, a treated/control (T/C) value of 155% was obtained. MS-209 also enhanced the chemotherapeutic effect of ADM in P388/ADM-bearing mice. The most prominent effects were obtained when MS-209 was given with 2 mg/kg ADM, yielding T/C values of 150%–194% for the combined treatment at an MS-209 dose of 200–450 mg/kg. MS-209 inhibited [3H]-azidopine photolabeling of P-glycoprotein efficiently. Furthermore, the accumulation of ADM in K562/ADM cells was increased more eficiently by MS-209 than by verapamil. These results indicate that MS-209, like verapamil, directly interacts with P-glycoprotein and inhibits the active efflux of antitumor agents, thus overcoming multidrug resistance in vitro and in vivo.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Carmichael JD, Degraff WG, Gazdar AF, Minna JD, Michell JB (1987) Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res 47: 936–942

    CAS  PubMed  Google Scholar 

  2. Cornwell MM, Safa AR, Felsted RL, Gottesman MM, Pastan I (1986) Membrane vesicles from multidrug-resistant cancer cells contain a 150- to 170-kDa protein detected by photoaffinity labeling. Proc Natl Acad Sci USA 83: 3847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Danø K (1973) Active outward transport of daunomycin in resistant Ehrlich ascites tumor cells. Biochim Biophys Acta 323: 466

    Article  PubMed  Google Scholar 

  4. Deffie AM, Bosman DJ, Goldenberg GJ (1989) Evidence for a mutant allele of the gene for DNA topoisomerase II in Adriamycin-resistant P388 murine leukemia cells. Cancer Res 49: 6879

    CAS  PubMed  Google Scholar 

  5. Fojo A, Akiyama S, Gottesman MM, Pastan I (1985) Reduced drug accumulation in multiple drug-resistant human KB carcinoma cell lines. Cancer Res 45: 3002

    CAS  PubMed  Google Scholar 

  6. Fukazawa N, Odate M, Suzuki T, Otsuka K, Sato W, Tsuruo T (1989) Novel heterocyclic compounds and anticancer-drug reinforcing agents containing them as effective components. European patent publication 0363212. European patent office, Munich

    Google Scholar 

  7. Hamada H, Tsuruo T (1986) Functional role for the 170- to 180-kDa glycoprotein specific to drug-resistant tumor cells as revealed by monoclonal antibodies. Proc Natl Acad Sci USA 83: 7785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Inaba M, Johnson RK (1977) Decreased retention of actinomycin D as the basis for cross-resistance in anthracyclineresistant sublines of P388 leukemia. Cancer Res 37: 4629

    CAS  PubMed  Google Scholar 

  9. Inaba M, Johnson RK (1978) Uptake and retention of Adriamycin and daunorubicin by sensitive and anthracyclineresistant subline of P388 leukemia. Biochem Pharmacol 27: 2123

    Article  CAS  PubMed  Google Scholar 

  10. Naito M, Tsuruo T (1989) Competitive inhibition by verapamil of ATP-dependent high affinity vincristine binding to the plasma membrane of multidrug-resistant K562 cells without calcium ion involvement. Cancer Res 49: 1452

    CAS  PubMed  Google Scholar 

  11. Naito M, Hamada H, Tsuruo T (1988) ATP/Mg2+-dependent binding of vincristine to the plasma membrane of multidrugresistant K562 cells. J Biol Chem 263: 11887

    CAS  PubMed  Google Scholar 

  12. Ramu A, Glaubiger D, Fuks Z (1984) Reversal of acquired resistance to doxorubicin in P388 murine leukemia by tamoxifen and other triparanol analogues. Cancer Res 44: 4392

    CAS  PubMed  Google Scholar 

  13. Riordan JR, Ling V (1985) Genetic and biochemical characterization of multidrug resistance. Pharmacol Ther 28: 51

    Article  CAS  PubMed  Google Scholar 

  14. Safa AR, Glover CJ, Meyers MB, Biedler JL, Felsted RL (1986) Vinblastine photoaffinity labeling of a high molecular weight surface membrane glycoprotein specific for multidrug-resistant cells. J Biol Chem 261: 6137

    CAS  PubMed  Google Scholar 

  15. Safa AR, Glover CJ, Meyers MB, Biedler JL, Felsted RL (1987) Identification of the multidrug resistance-related membrane glycoprotein as an acceptor for calcium channel blockers. J Biol Chem 262: 7884

    CAS  PubMed  Google Scholar 

  16. Sato W, Fukazawa N, Suzuki T, Yusa K, Tsuruo T (1991) Circumvention of multidrug resistance by a newly synthesized quinoline derivative, MS-073. Cancer Res 51: 2420

    CAS  PubMed  Google Scholar 

  17. Shen DW, Cardarelli C, Hwang J, Cornwell M, Richert N, Ishii S, Pastan I, Gottesman MM (1986) Multiple drug-resistant human KB carcinoma cells independently selected for high-level resistance to colchicine, Adriamycin, or vinblastine show changes in expression of specific proteins. J Biol Chem 261: 7762

    CAS  PubMed  Google Scholar 

  18. Skovsgaard T (1978) Mechanism of cross-resistance between vincristine and daunomycin in Ehrlich ascites tumor cells. Cancer Res 38: 4722

    CAS  PubMed  Google Scholar 

  19. Slater LM, Sweet P, Stupecky M, Gupta S (1986) Cyclosporin A reverses vincristine and daunorubicin resistance in acute lymphatic leukemia in vitro. J Clin Invest 77: 1405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sugimoto Y, Nishimura T, Suzuki H, Tanaka N (1981) Evidence of altered influx of Adriamycin into anthracycline-resistant cells. J Antibiot (Tokyo) 34: 1064

    Article  CAS  Google Scholar 

  21. Tsuruo T (1989) Circumvention of drug resistance with calcium channel blockers and monoclonal antibodies. In: Ozols RF (ed) Drug resistance in cancer therapy. Kluwer, Boston, p 73

    Chapter  Google Scholar 

  22. Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y (1981) Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 41: 1967

    CAS  PubMed  Google Scholar 

  23. Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y (1982) Increased accumulation of vincristine and adriamycin in drug-resistant tumor cells following incubation with calcium antagonists and calmodulin inhibitors. Cancer Res 42: 4730

    CAS  PubMed  Google Scholar 

  24. Tsuruo T, Iida H, Nojiri M, Tsukagoshi S, Sakurai Y (1983) Circumvention of vincristine and Adriamycin resistance in vitro and in vivo by calcium influx blockers. Cancer Res 43: 2905

    CAS  PubMed  Google Scholar 

  25. Tsuruo T, Iida H, Kikatani Y, Yokota K, Tsukagoshi S, Sakurai Y (1984) Effects of quinidine and related compounds on cytotoxicity and cellular accumulation of vincristine and adriamycin in drug-resistant tumor cells. Cancer Res 44: 4303

    CAS  PubMed  Google Scholar 

  26. Tsuruo T, Saito HI, Kawabata H, Oh-hara T, Hamada H, Utakoji T (1986) Characteristics of resistance to Adriamycin in human myelogenous leukemia K562 resistant to Adriamycin and in isolated clones. Jpn J Cancer Res 77: 682

    CAS  PubMed  Google Scholar 

  27. Twentyman PR (1988) Modification of cytotoxic drug resistance by non-immuno-suppressive cyclosporines. Br J Cancer 57: 254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yang C-PH, Mellado W, Horwitz SB (1988) Azidopine photoaffinity labeling of multidrug resistant-associated glycoprotein. Biochem Pharmacol 37: 1417

    Article  CAS  PubMed  Google Scholar 

  29. Yusa K, Tsuruo T (1989) Reversal mechanism of multidrug resistance by verapamil: direct binding of verapamil to P-glycoprotein on specific sites and transport of verapamil outward across the plasma membrane of K562/ADM cells. Cancer Res 49: 5002

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Biological Science, Mitsui Pharmaceuticals, Inc., 297, Mobara-shi, Chiba, Japan

    Wakao Sato, Osamu Nakanishi, Makoto Baba & Osamu Yano

  2. Life Science Laboratory, Mitsui Toatsu Chemicals, Inc., 297, Mobara-shi Chiba, Japan

    Nobuyuki Fukazawa & Tsuneji Suzuki

  3. Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, 113, Tokyo, Japan

    Mikihiko Naito & Takashi Tsuruo

  4. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Kami-ikebukuro, Toshima-ku, 170, Tokyo, Japan

    Takashi Tsuruo

Authors
  1. Wakao Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nobuyuki Fukazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Osamu Nakanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Makoto Baba
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tsuneji Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Osamu Yano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mikihiko Naito
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takashi Tsuruo
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This work was supported by grants-in-aid from the Ministry of Education Science and Culture, Japan

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sato, W., Fukazawa, N., Nakanishi, O. et al. Reversal of multidrug resistance by a novel quinoline derivative, MS-209. Cancer Chemother. Pharmacol. 35, 271–277 (1995). https://doi.org/10.1007/BF00689444

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00689444

Key words

Search

Navigation