INTERLEUKIN-6 DIFFERENTIALLY POTENTIATES THE ANTITUMOR EFFECTS OF TAXOL AND VINBLASTINE IN U266 HUMAN MYELOMA CELLS

Newer therapeutic strategies for the treatment of multiple myeloma hav e focused on antagonizing the growth-promoting functions of interleuki n 6 (IL-6), In this study, we examined the antitumor effects of two me chanistically different microtubule poisons, Taxol and vinblastine, in U266 human myeloma cells and determined whether IL-6 altered these ef fects, Taxol and vinblastine led to a dose-dependent inhibition of [H- 3]thymidine incorporation and altered the DNA distribution pattern of U266 cells, Both drugs led to an increase in the proportion of cells i n the sub-G, fraction (<2N DNA), However, at the IC50 concentration, v inblastine, but not Taxol, increased the percentage of cells in the G( 2)-M phase of the cell cycle, In the presence of IL-6, the DNA distrib ution pattern induced by Taxol or vinblastine was altered, Whereas IL- 6 augmented the sub-G, fraction and G(2)-M phase for Taxol-treated cel ls, only the G(2)-M phase was increased for vinblastine-treated cells, Furthermore, IL-6 enhanced the cytotoxicity of both drugs, which beca me evident only during recovery in cytokine-free and drug-free medium, However, the cytotoxicity of Taxol was augmented to a significantly g reater extent than that of vinblastine (P < 0.001), Immunostaining wit h antibodies to ol-tubulin and mitogen-activated protein kinase reveal ed colocalization of these two proteins within microtubule asters, In the presence of IL-6, the number of cells containing microtubule aster s increased for Tar;ol treatment, but not for vinblastine treatment, T hese data indicate that IL-6 leads to differential modulation of the c ytotoxicity of Taxol and vinblastine in U266 cells, Whereas recruitmen t of cells in the S phase of the cell cycle represents a major mechani sm by which IL-6 potentiates the cytotoxicity of vinblastine, augmenta tion of the cytotoxicity of Taxol involves additional mechanisms, Furt hermore, our data suggest that the microtubule-associated form of mito gen-activated protein kinase may play a role in IL-6-mediated enhancem ent of the cytotoxicity of Taxol, The clinical implications of these f indings are discussed.