International Journal of Hematology

, Volume 99, Issue 6, pp 726–736 | Cite as

Suitable drug combination with bortezomib for multiple myeloma under stroma-free conditions and in contact with fibronectin or bone marrow stromal cells

  • Jiro Kikuchi
  • Daisuke Koyama
  • Harumi Y. Mukai
  • Yusuke Furukawa
Original Article
First Online:
Received:
Revised:
Accepted:

Abstract

Several clinical trials have demonstrated the effectiveness of bortezomib in combination with various anti-myeloma agents; however, no definitive information is available regarding drugs best suited for use in combination with bortezomib. Using isobologram analysis, we investigated the combined effects of bortezomib with four key anti-myeloma drugs (melphalan, cyclophosphamide, doxorubicin and lenalidomide), which represent components of major bortezomib-based regimens with corticosteroids, in three myeloma cell lines (U266, RPMI8226 and KMS-12BM) under various conditions. Melphalan showed the best performance with bortezomib under all culture conditions tested (liquid culture, on fibronectin-coated plates, and co-culture with bone marrow stromal cells), whereas cyclophosphamide was antagonistic with bortezomib especially in the presence of stromal cells. Doxorubicin showed additive effects under stroma-free conditions and in contact with fibronectin, but was rather antagonistic in the presence of stromal cells. In contrast, lenalidomide exerted the most favorable effect with bortezomib in contact with stromal cells. Consistent with these results, caspase-3 was activated more strongly by melphalan than by other agents in combination with bortezomib. Moreover, bortezomib-induced up-regulation of CHOP was readily enhanced by lenalidomide in contact with stromal cells. The present findings may provide fundamental information for the selection of bortezomib-based regimens for myeloma patients.

Keywords

Bortezomib Drug combination Isobologram Bone marrow microenvironment 
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Notes

Acknowledgments

The authors are grateful to Drs. Yasuhiko Kano (Tochigi Cancer Center) and Kaoru Noborio-Hatano (Jichi Medical School) for their technical advice regarding the generation of the isobologram of Steel and Peckham, Professor Kiyoshi Ando (Tokai University) for technical advice regarding the establishment of the co-culture system, and Ms. Akiko Yonekura for technical assistance. This work was supported in part by the High-Tech Research Center Project for Private Universities: Matching Fund Subsidy from MEXT, a Grant-in-Aid for Scientific Research from JSPS, and research grants from Japan Leukemia Research Fund, Osaka Cancer Foundation (to YF and JK), Takeda Science Foundation, Kano Foundation and Mitsui Life Social Welfare Foundation (to JK). YF is a winner of the Award in Aki’s Memory from the International Myeloma Foundation Japan.

Conflict of interest

YF received research funding and honoraria from Janssen Pharmaceutical K.K. The other authors have no conflicts of interest.

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Copyright information

© The Japanese Society of Hematology 2014

Authors and Affiliations

  • Jiro Kikuchi
    • 1
  • Daisuke Koyama
    • 1
  • Harumi Y. Mukai
    • 2
  • Yusuke Furukawa
    • 1
  1. 1.Division of Stem Cell Regulation, Center for Molecular MedicineJichi Medical UniversityTochigiJapan
  2. 2.Medical Affairs DivisionJanssen Pharmaceutical K.K.TokyoJapan

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