Retinoids in chemoprevention and differentiation therapy

Retinoids are essential for the maintenance of epithelial differentiation. As such, they play a fundamental role in chemoprevention of epithelial carc inogenesis and in differentiation therapy. Physiological retinoic acid is o btained through two oxidation steps from dietary retinol, i.e. retinol-->re tinal-->retinoic acid. The latter retinal-->retinoic acid step is irreversi ble and eventually marks disposal of this essential nutrient, through cytoc hrome P450-dependent oxidative steps. Mutant mice deficient in aryl hydroca rbon receptor (AHR) accumulate retinyl palmitate, retinol and retinoic acid . This suggests a direct connection between the AHR and retinoid homeostasi s. Retinoids control gene expression through the nuclear retinoic acid rece ptors (RARs) alpha, beta and gamma and 9-cis-retinoic acid receptors alpha, beta and gamma, which bind with high affinity the natural ligands all-tran s-retinoic acid and 9-cis-retinoic acid, respectively. Retinoids are effect ive chemopreventive agents against skin, head and neck, breast, liver and o ther forms of cancer. Differentiation therapy of acute promyelocytic leukem ia (APL) is based on the ability of retinoic acid to induce differentiation of leukemic promyelocytes. Patients with relapsed, retinoid-resistant APL are now being treated with arsenic oxide, which results in apoptosis of the leukemic cells. Interestingly, induction of differentiation in promyelocyt es and consequent remission of APL following retinoid therapy depends on ex pression of a chimeric PML-RAR alpha fusion protein resulting from a t(15;1 7) chromosomal translocation, This protein functions as a dominant negative against the function of both PML and RARs and its overexpression is able t o recreate the phenotypes of the disease in transgenic mice. The developmen t of new more effective and less toxic retinoids, alone or in combination w ith other drugs, may provide additional avenues for cancer chemoprevention and differentiation therapy.