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Antimyeloma effects of arsenic trioxide are enhanced by melphalan, bortezomib and ascorbic acid
Author(s) -
Campbell Richard A.,
Sanchez Eric,
Steinberg Jeffrey A.,
Baritaki Stavroula,
Gordon Melinda,
Wang Cathy,
Shalitin Dror,
Chen Haiming,
Pang Shen,
Bonavida Benjamin,
Said Jonathan,
Berenson James R.
Publication year - 2007
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2007.06675.x
Subject(s) - arsenic trioxide , bortezomib , melphalan , in vivo , multiple myeloma , cancer research , in vitro , ascorbic acid , medicine , pharmacology , chemistry , apoptosis , biochemistry , biology , microbiology and biotechnology , food science
Summary Arsenic trioxide (ATO) induces apoptosis of malignant plasma cells through multiple mechanisms, including inhibition of DNA binding by nuclear factor kappa‐B, a key player in the development of chemoresistance in multiple myeloma (MM). This activity suggests that ATO may be synergistic when combined with other active antimyeloma drugs. To evaluate this, we examined the antimyeloma effects of ATO alone and in combination with bortezomib, melphalan and ascorbic acid (AA) both in vitro and in vivo using a severe combined immunodeficient (SCID)‐hu murine myeloma model. Marked synergistic antimyeloma effects were demonstrated when human MM Los Angeles xenograft IgG lambda light chain (LAG λ ‐1) cells were treated in vitro with ATO and any one of these agents. SCID mice bearing human MM LAG λ ‐1 tumours were treated with single‐agent ATO, bortezomib, melphalan, or AA, or combinations of ATO with either bortezomib or melphalan and AA. Animals treated with any of these drugs alone showed tumour growth and increases in paraprotein levels similar to control mice, whereas animals treated with ATO‐containing combinations showed markedly suppressed tumour growth and significantly reduced serum paraprotein levels. These in vitro and in vivo results suggest that addition of ATO to other antimyeloma agents may result in improved outcomes for patients with relapsed or refractory MM.