Combination therapy with interleukin-6 receptor superantagonist Sant7 and dexamethasone induces antitumor effects in a novel SCID-hu In vivo model of human multiple myeloma.
Interleukin-6 (IL-6) protects multiple myeloma cells against apoptosis induced by glucocorticoids. Here, we investigated whether inhibition of the IL-6 signaling pathway by the IL-6 receptor superantagonist Sant7 enhances the in vivo antitumor effects of dexamethasone on the IL-6-dependent multiple myeloma cell line INA-6. For this purpose, we used a novel murine model of human multiple myeloma in which IL-6-dependent INA-6 multiple myeloma cells were directly injected into human bone marrow implants in severe combined immunodeficient (SCID) mice (SCID-hu). The effect of in vivo drug treatments on multiple myeloma cell growth was monitored by serial determinations of serum levels of soluble IL-6 receptor (shuIL-6R), which is released by INA-6 cells and served as a marker of tumor growth. In SCID-hu mice engrafted with INA-6 cells, treatment with either Sant7 or dexamethasone alone did not induce significant reduction in serum shuIL-6R levels. In contrast, the combination of Sant7 with dexamethasone resulted in a synergistic reduction in serum shuIL-6R levels after 6 consecutive days of treatment. Gene expression profiling of INA-6 cells showed down-regulation of proliferation/maintenance and cell cycle control genes, as well as up-regulation of apoptotic genes in multiple myeloma cells triggered by Sant7 and dexamethasone combination. In vitro colony assays showed inhibition of myeloid and erythroid colonies from normal human CD34(+) progenitors in response to dexamethasone, whereas Sant7 neither inhibited colony growth nor potentiated the inhibitory effect of dexamethasone. Taken together, these results indicate that inhibition of IL-6 signaling by Sant7 significantly potentiates the therapeutic action of dexamethasone against multiple myeloma cells, providing the preclinical rationale for clinical trials of Sant7 in combination with dexamethasone to improve patient outcome in multiple myeloma.
Tassone
Pierfrancesco
P
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts 02115, USA.
Neri
Paola
P
Burger
Renate
R
Savino
Rocco
R
Shammas
Masood
M
Catley
Laurence
L
Podar
Klaus
K
Chauhan
Dharminder
D
Masciari
Serena
S
Gozzini
Antonella
A
Tagliaferri
Pierosandro
P
Venuta
Salvatore
S
Munshi
Nikhil C
NC
Anderson
Kenneth C
KC
D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D003114:Colony-Forming Units Assay; D003907:Dexamethasone / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D018952:Antigens, CD34; D018931:Antineoplastic Agents, Hormonal; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; C432252:SANT-7; D003907:Dexamethasone