Skip to main content
SpringerLink
Log in

Synergistic Growth Inhibition of YM529 with Biologic Response Modifiers (BRMs) in Myeloma Cells

  • Case Report
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Bisphosphonates (BPs) are effective in the management of bone disease in patients with multiple myeloma. Recent reports have suggested that they may also have an antitumor activity. YM529 is a new synthetic BP with more than 1000 times the bone resorption inhibitory activity of pamidronate. To clarify the direct effects of YM529 on myeloma cells, the cell proliferation and cell cycle perturbation were analyzed using 12 myeloma cell lines established in our laboratory. The growth inhibition was dose dependent. The cells accumulated in [2n≪4n] of the cell cycle and subsequently formed an apoptotic sub-G1 fraction. Combined treatment with all-trans retinoic acid, thalidomide, or interferon-α enhanced the growth inhibitory effects of YM529 on these cells. However, there were no remarkable effects of YM529 on the messenger RNA expression for angiogenic factors, cell cycle regulators, or cytokines related to myeloma cells. These results indicate that YM529 is beneficial not only to bone lesions but also for its direct antitumor effects on myeloma cells.

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. Callander NS,Roodman GD. Myeloma bone disease.Semin Hematol. 2001;38:276–285.

    Article  CAS  PubMed  Google Scholar 

  2. Rodan GA, Fleisch HA. Bisphosphonates: mechanisms of action.J Clin Invest. 1996;97:2692–2696.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Shipman CM, Croucher PI, Russell RG, Helfrich MH, Rogers MJ. The bisphosphonate incadronate (YM175) causes apoptosis of human myeloma cells in vitro by inhibiting the mevalonate pathway.Cancer Res. 1998;58:5294–5297.

    PubMed  CAS  Google Scholar 

  4. Dhodapkar MV, Singh J, Mehta J, et al. Anti-myeloma activity of pamidronate in vivo.Br J Haematol. 1998;103:530–532.

    Article  CAS  PubMed  Google Scholar 

  5. Berenson JR, Lichtenstein A, Porter L, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group.J Clin Oncol. 1998; 16:593–602.

    Article  CAS  PubMed  Google Scholar 

  6. Shipman CM, Rogers MJ, Apperley JF, Russell RG, Croucher PI. Bisphosphonates induce apoptosis in human myeloma cell lines: a novel anti-tumour activity.Br J Haematol. 1997;98:665–672.

    Article  CAS  PubMed  Google Scholar 

  7. Aparicio A, Gardner A, Tu Y, Savage A, Berenson J, Lichtenstein A. In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates.Leukemia 1998;12:220–229.

    Article  CAS  PubMed  Google Scholar 

  8. Derenne S, Amiot M, Barille S, et al. Zoledronate is a potent inhibitor of myeloma cell growth and secretion of IL-6 and MMP-1 by the tumoral environment.J Bone Miner Res. 1999;14:2048–2056.

    Article  CAS  PubMed  Google Scholar 

  9. Kunzmann V, Bauer E, Feurle J,Weissinger F,Tony HP,Wilhelm M. Stimulation of gammadelta T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma.Blood.2000;86:384–392.

    Google Scholar 

  10. Usui T, Kawakami R, Watanabe T, Higuchi S. Sensitive determination of a novel bisphosphonate, YM529, in plasma, urine and bone by high-performance liquid chromatography with fluorescence detection.J Chromatogr. 1994;652:67–72.

    Article  CAS  PubMed  Google Scholar 

  11. Sasaki A, Kitamura K, Alcalde RE, et al. Effect of a newly developed bisphosphonate, YH529, on osteolytic bone metastases in nude mice.Int J Cancer. 1998;77:279–285.

    Article  CAS  PubMed  Google Scholar 

  12. Takahashi R, Shimazaki C, Inaba T, et al. A newly developed bisphosphonate, YM529, is a potent apoptosis inducer of human myeloma cells.Leuk Res. 2001;25:77–83.

    Article  CAS  PubMed  Google Scholar 

  13. Tassone P, Forciniti S, Gallea E, et al. Growth inhibition and synergistic induction of apoptosis by zoledronate and dexamethasone in human myeloma cell lines.Leukemia. 2000;14:841–844.

    Article  CAS  PubMed  Google Scholar 

  14. Jagdev SP, Coleman RE, Shipman CM, Rostami-H A, Croucher PI. The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel.Br J Cancer.2001;84:1126–1134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Musto P, Sajeva MR, Sanpaolo G, DArena G, Scalzulli PR, Carotenuto M. All-trans retinoic acid in combination with alpha-interferon and dexamethasone for advanced multiple myeloma.Haematologica. 1997;82:354–356.

    PubMed  CAS  Google Scholar 

  16. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma.N Engl J Med. 1999;341:1565–1571.

    Article  CAS  PubMed  Google Scholar 

  17. Myeloma Trialists’ Collaborative Group. Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients.Br J Haematol. 2001;113: 1020–1034.

    Article  Google Scholar 

  18. Otsuki T, Yamada O, Yata K, et al. Genetic and biological characterization of human myeloma cell lines: an overview of the lines established at Kawasaki Medical School.Gene Funct Dis. 2000;1:48–56.

    Article  CAS  Google Scholar 

  19. Otsuki T, Yamada O, Sakaguchi H,et al. Human myeloma cell apoptosis induced by interferon-α.Br J Haematol. 1998;103:518–529.

    Article  CAS  PubMed  Google Scholar 

  20. Otsuki T, Yata K, Sakaguchi H, et al. IL-10 abolishes the growth inhibitory effects of all trans retinoic acid (ATRA) on human myeloma cells.Br J Haematol. 2002;116:787–795.

    Article  CAS  PubMed  Google Scholar 

  21. Hideshima T, Chauhan D, Shima Y, et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy.Blood. 2000;96:2943–2950.

    PubMed  CAS  Google Scholar 

  22. Berger LC, Hawley RG. Interferon-beta interrupts interleukin-6-dependent signaling events in myeloma cells.Blood. 1997;89: 261–271.

    PubMed  CAS  Google Scholar 

  23. Tanaka K, Otsuki T, Sonoo H, et al. Semi-quantitative comparison of the differentiation markers and sodium iodide symporter in papillary thyroid carcinomas using RT-PCR method.Eur J Endocrinol. 2000;142:340–346.

    Article  CAS  PubMed  Google Scholar 

  24. Sato M, Grasser W, Endo N, et al. Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultra-structure.J Clin Invest. 1991;88:2095–2105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hideshima T, Chauhan D, Shima Y, et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy.Blood. 2000;96:2943–2950.

    PubMed  CAS  Google Scholar 

  26. Chen YH, Lavelle D, DeSimone J, Uddin S, Platanias LC, Hankewych M. Growth inhibition of a human myeloma cell line by all-trans retinoic acid is not mediated through downregulation of interleukin-6 receptors but through upregulation of p21 (WAF1).Blood. 1999;94:251–259.

    PubMed  CAS  Google Scholar 

  27. Dallas SL, Garrett IR, Oyajobi BO, et al. Ibandronate reduces osteolytic lesions but not tumor burden in a murine model of myeloma bone disease.Blood. 1999;93:1697–1706.

    PubMed  CAS  Google Scholar 

  28. Shipman CM, Vanderkerken K, Rogers MJ, et al. The potent bisphosphonate ibandronate does not induce myeloma cell apoptosis in a murine model of established multiple myeloma.Br J Haematol. 2000;111:283–286.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology, Department of Internal Medicine, Kawasaki Medical School, 577 Kurashiki, Okayama, Japan

    Kenichiro Yata, Osamu Yamada, Hideho Wada & Takashi Sugihara

  2. Department of Hygiene, Kawasaki Medical School, Japan

    Takemi Otsuki

  3. Department of Care Work, Kawasaki College of Allied Health Professions, Okayama, Japan

    Yoshihito Yawata

Authors
  1. Kenichiro Yata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takemi Otsuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Osamu Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hideho Wada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshihito Yawata
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takashi Sugihara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenichiro Yata.

About this article

Cite this article

Yata, K., Otsuki, T., Yamada, O. et al. Synergistic Growth Inhibition of YM529 with Biologic Response Modifiers (BRMs) in Myeloma Cells. Int J Hematol 75, 534–539 (2002). https://doi.org/10.1007/BF02982119

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02982119

Key words

Search

Navigation