Receptor selective synthetic retinoids as potential cancer chemotherapy agents

For many years, the vitamin A metabolite retinoic acid (RA) has been known to have profound effects on development, cellular proliferation and differentiation, and tumor growth and invasion. The wide-ranging effects of RA on cellular proliferation and migration have made it a useful chemotherapeutic agent in the treatment of many types of cancer. In the last fifteen years, with the discovery of nuclear receptors for RA, the molecular basis for the effects of this molecule has become apparent. Retinoic acid receptors (RAR) are members of a superfamily of ligand dependent transcription factors that interact with an increasingly large array of coactivators and repressors to regulate target gene expression through binding to cognate recognition sequences in the promoters of these genes. Alterations in RAR expression and function have been demonstrated in many types of cancer. The translocation of RARalpha with PML or PLZF genes in acute promyelocytic leukemia is a paradigm of the role of RARs in cancer biology. In addition, the development of receptor selective synthetic retinoids has greatly expanded our knowledge of RAR function in tumor cells and provided additional treatment options for cancer patients. This review will examine the development of receptor selective retinoids, their uses to date, and future potential.