The bone marrow stromal environment is a major factor in myeloma cell resistance to dexamethasone.
Dexamethasone (Dex), which is often used for the treatment of multiple myeloma, produces rapid reductions in tumor mass and improvement in disease symptoms; however, it is not curative, and drug-resistant cells eventually emerge. To elucidate this apparent paradox, we tested the effect of the bone marrow environment on myeloma cell response to this drug. To determine whether bone marrow stroma provides sufficient amounts of interleukin (IL)-6 to protect myeloma cells against the effects of Dex, we compared the production of IL-6 by marrow stromal cells from four myeloma patients before, during, and after exposure to 10(-7) M Dex, and found that even in the presence of this drug, stromal cells continued to produce IL-6, albeit in reduced concentrations. We tested the ability of stromal cells to protect myeloma cells, purified from the bone marrow of seven patients by cell sorting on the basis of CD38 and CD45 expression, and two light-scatter parameters, from Dex-induced apoptosis. In contrast to mature CD38+CD45- cells, which were not protected, coculture with stroma very effectively protected immature CD38+CD45+ myeloma cells from Dex. These data may explain the palliative efficacy of Dex treatment and provide a rationale for combining IL-6 antagonists with Dex to overcome the IL-6-mediated resistance of immature tumor cells.
Grigorieva
I
I
The Arkansas Cancer Research Center, Department of Medicine, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
Thomas
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X
Epstein
J
J
D000937:Antigen-Antibody Reactions; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000187:drug effects*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003907:Dexamethasone / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000032:analysis; D012995:Solubility; D017154:Stromal Cells / Q000187:drug effects; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D019947:Receptors, Interleukin-6; D003907:Dexamethasone