Retinoids, including retinoic acid (RA), are naturally occurring and synthetic analogs of vitamin A that inhibit cell growth and induce cell differentiation in many experimental tumor models. Differentiation of the human myelogenous leukemia cell line HL-60 by RA led to the finding that cells from patients with acute promyelocytic leukemia (APL) are terminally differentiated by RA. One mechanism for the activity of RA in a variety of cell types involves the RA nuclear receptors (RA receptors [RARs] and retinoid X receptors), which have specific high-affinity binding sites for RA and some of its metabolites. Other mechanisms may also be involved in RA-induced differentiation. Recent studies suggest that RA acylation (retinoylation) may be involved in the RA induction of differentiation in leukemia cells. Combinations of RA with cyclic adenosine monophosphate (cAMP)-elevating agents led to synergistically induced differentiation of HL-60 cells. The lower doses of RA needed in combination therapy are unlikely to lead to RA resistance, a major limitation of RA therapy in APL. In vitro studies suggest that combinations of RA with either PGE or the butyric acid (BA) prodrug tributyrin (TB) may be useful in differentiation therapy for APL and other malignancies. This is a US government work. There are no restrictions on its use.