INHIBITION OF MYELOMA CELL-GROWTH BY DEXAMETHASONE AND ALL-TRANS-RETINOIC ACID - SYNERGY THROUGH MODULATION OF INTERLEUKIN-6 AUTOCRINE LOOPAT MULTIPLE SITES

Interleukin-6 (IL-6)/IL-6 receptor (IL-6R) plays a major role in autoc rine/paracrine growth regulation of myeloma cells. We investigated the effect of dexamethasone and all-trans retinoic acid, previously shown to modulate IL-6/IL-6R, on the in vitro growth of a human myeloma cel l line, OPM-2. both agents inhibited the clonogenic growth and H-3-thy midine incorporation in a concentration-dependent fashion. Isobologram and median effect analysis showed a strong synergy between these two agents with a combination index in the range of 0.2 to 0.6. Both agent s decreased the labeling index and the cell fraction in S and G(2)/M p hases, suggesting a block in G(1)-S phase transition. The clonogenic g rowth was stimulated by exogenous IL-6 and was inhibited by monoclonal antibody to IL-6, suggesting an autocrine function of IL-6. The effec t of dexamethasone but not all-trans retinoic acid was completely reve rsed by exogenous IL-6. Dexamethasone increased, while all-trans retin oic acid reduced, IL-6R but not gp130 mRNA expression. Their combinati on caused a net reduction in IL-6R mRNA, Cellular IL-6R density was al tered correspondingly without changes in the binding affinity, IL-6 mR NA expression was reduced by dexamethasone and the combination, but wa s not affected by retinoic acid alone. However, IL-6 secretion into cu lture supernatant was abolished by both agents. A survey of 4 addition al human myeloma cells showed that 1 was sensitive to both, 1 was sens itive to one agent only, and 2 were resistant to both. The study demon strates the possibility of regulating myeloma cell growth through modu lation of IL-6/IL-6R autocrine/paracrine loop and the principle of ach ieving a synergistic effect by blocking this loop at multiple sites. ( C) 1996 by The American Society of Hematology.