Retinoids as Anti-Cancer Agents

Abstract: Retinoids, synthetic and natural analogs of retinoic acid, exhibit potent growth inhibitory and cell differentiation activities which account for their beneficial effects in cancer in ex vivo and in vivo models. These simple molecules with pleiotropic effects have shown potential as therapeutic agents for the treatment of cancer either alone or in combination with other agents. Retinoids regulate the growth of various cell types by directly modulating the expression of responsive genes through nuclear retinoid receptors (RARs and RXRs), which are ligand dependent transcription factors. The translo­ cation of RARCX in acute pro-myelocytic leukemia, decreased expression of RARP and reduced activity of the •RARP promoter in various tumors and cancer cell lines, and restoration of retinoid sensitivity to cancer cells by RAR expression vector transfection, are all indicative of the direct involvement of RAR malfunction in the process of tumorigenesis and also suggest a role for RARs as ligand dependent tumor suppressors. The current use of retinoids in cancer is limited because of their associated toxicities and lack of efficacy at tolerated doses. In order to improve the therapeutic index of retinoids, various strategies are currently being employed, e.g., receptor selective retinoids, anti-AP! selective retinoids and combination therapies. The development of novel retinoids along with an increased understanding of the biological functions and mechanisms of action of retinoid receptors are likely to usher in a new era of retinoid therapy of cancers.