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Vorinostat enhances the antimyeloma effects of melphalan and bortezomib
Author(s) -
Campbell Richard A.,
Sanchez Eric,
Steinberg Jeffrey,
Shalitin Dror,
Li ZhiWei,
Chen Haiming,
Berenson James R.
Publication year - 2010
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/j.1600-0609.2009.01384.x
Subject(s) - vorinostat , bortezomib , melphalan , in vivo , multiple myeloma , pharmacology , medicine , cancer research , chemistry , histone deacetylase , histone , biology , biochemistry , microbiology and biotechnology , gene
Objectives: Examine the antitumor activity of the histone deacetylase inhibitor vorinostat’s antitumor activity against multiple myeloma (MM) using cell lines and a murine xenograft model. Methods: RPMI8226, U266, and MM1S cells were cultured for 48 h in the presence of media, vorinostat, melphalan, or bortezomib alone, or combinations of vorinostat with melphalan or bortezomib. Cell proliferation was measured using the MTS [3‐(4,5‐dimethylthiazol‐2yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfphophenyl)‐2H‐tetrazolium, inner salt] assay. Severe combined immunodeficient mice bearing LAGκ‐1B tumors were treated with vorinostat [30, 60, or 100 mg/kg daily for five consecutive days per week (qd×5d), 100 or 300 mg/kg daily for 2 d/wk (qd×2d)], melphalan (1, 3, or 10 mg/kg qd×1d), bortezomib (0.25 or 0.5 mg/kg qd×2d), or combinations thereof for 35 d. Tumor growth was determined via measurement of human immunoglobulin G (hIgG) levels and tumor volume. Results and Conclusions: Vorinostat enhanced the anti‐MM effects of melphalan and bortezomib in vitro . Synergism was observed with vorinostat and melphalan in RPMI8226 and U266 cell lines. Vorinostat 100 mg/kg in combination with melphalan 3 mg/kg resulted in significant inhibition of tumor growth in vivo , compared with control (tumor volume P = 0.0001; hIgG P = 0.0001), single‐agent vorinostat (tumor volume P = 0.0025; hIgG P = 0.0137), and single‐agent melphalan (tumor volume P = 0.0043; hIgG P = 0.0426). Vorinostat also enhanced the antimyeloma effects of bortezomib in vivo . Vorinostat enhances the anti‐MM activity of melphalan and bortezomib in vitro and in vivo . This study provides rationale for further evaluation of vorinostat in combination with chemotherapeutic agents and bortezomib for the treatment of MM.