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Synergistic Cytotoxicity Exhibited by Combination Treatment of Selective Retinoid Ligands with Taxol (Paclitaxel)

Department of Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000 [V. V. H., D. Y., C. R., M. V. L., M. M. G.]; Wallingford Discovery Chemistry, Bristol-Myers Squibb, Wallingford, Connecticut 03492-1996 [C. F. Z.]; and Drug Discovery Chemistry, Bristol-Myers Squibb, Candiac (Quebec), J5R 1J1 Canada [J. P. D., P. L., A. M.]

The focus of this study was to develop retinoic acid receptor (RAR) RAR/ß selective agonists with anticancer efficacy and reduced toxicity associated with RAR activity. In these studies, we report the identification and characterization of high-affinity RAR/ß selective agonists with limited RAR activity. These compounds inhibited human tumor cell line proliferation with similar efficacy to that observed for a pan-RAR agonist. However, for most tumor cell lines, the efficacy of these compounds was restricted to the micromolar range. To determine whether the RAR/ß selective agonists could be additive or synergistic with existing agents, we investigated the effects of combining RAR/ß selective agonists with various cytotoxic agents. Our results showed that the /ß selective retinoids dramatically lowered the effective dose of Taxol needed to induce cytotoxicity of a wide range of tumor cell lines. This synergy was specific to tubulin-modifying agents and could not be observed with a variety of other cytotoxic agents of diverse function. Examination of pathways common to Taxol and retinoid signaling revealed that this synergy was related in part to effects on Bcl-2 expression/phosphorylation as well as the activity of the c-Jun NH₂-terminal kinase and activator protein-1. In contrast, the tubulin polymerization induced by Taxol was not further affected by cotreatment with a variety of retinoid receptor ligands. These observations indicate that potent RAR/ß selective agonists may be of therapeutic benefit in combination with Taxol therapy.

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