Cytodifferentiation by retinoids, a novel therapeutic option in oncology: rational combinations with other therapeutic agents.

Retinoic acid (RA) and derivatives are promising antineoplastic agents endowed with both therapeutic and chemopreventive potential. Although the treatment of acute promyelocytic leukemia with all-trans retinoic acid is an outstanding example, the full potential of retinoids in oncology has not yet been explored and a more generalized use of these compounds is not yet a reality. One way to enhance the therapeutic and chemopreventive activity of RA and derivatives is to identify rational combinations between these compounds and other pharmacological agents. This is now possible given the information available on the biochemical and molecular mechanisms underlying the biological activity of retinoids. At the cellular level, the antileukemia and anticancer activity of retinoids is the result of three main actions, cytodifferentiation, growth inhibition, and apoptosis. Cytodifferentiation is a particularly attractive modality of treatment and differentiating agents promise to be less toxic and more specific than conventional chemotherapy. This is the result of the fact that cytotoxicity is not the primary aim of differentiation therapy. At the molecular level, retinoids act through the activation of nuclear retinoic acid receptor-dependent and -independent pathways. The cellular pathways and molecular networks relevant for retinoid activity are modulated by a panoply of other intracellular and extracellular pathways that may be targeted by known drugs and other experimental therapeutics. This chapter aims to summarize and critically discuss the available knowledge in the field.