Retinoic acid derivatives have shown their greatest benefit in acute promyelocytic leukemia, but have also demonstrated pre-clinical anti-cancer effects in some solid tumors. Histone deacetylase inhibitors, by upregulating gene expression, are able to limit cancer cell proliferation and induce apoptosis. The combination of all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor valproic acid has been previously studied in hematologic malignancies. We conducted a phase I two-step dose escalation trial of the liposomal ATRA analog ATRA-IV and divalproex sodium (Depakote) in nine patients with advanced solid tumors refractory to prior therapy. Side effects attributed to therapy had a severity <or=grade 2="" and="" included="" skin="" toxicity="" thrombocytopenia.="" the="" best="" disease="" response="" seen="" was="" stabilization="" in="" one="" patient.="" expression="" of="" cellular="" retinoic="" acid="" binding="" protein-2="" peripheral="" blood="" mononuclear="" cells="" detected="" as="" a="" marker="" drug="" effect.="" maximum="" tolerated="" dose="" (mtd)="" both="" drugs="" combination="" could="" not="" be="" established="" due="" to="" early="" closure="" trial="" resulting="" from="" halt="" commercial="" availability="" atra-iv.<="" p="">