Synthetic retinoids as potential antitumour agents

The retinoids, natural or synthetic derivatives of vitamin A, exhibit a variety of biological effects that may have implications in cancer chemoprevention and therapy. The chemopreventative action of classical retinoids has been ascribed to receptor-mediated modulation of a range of biological processes, including cell differentiation and proliferation. The therapeutic interest of several synthetic retinoids (also known as retinoid-related molecules) is related to their proapoptotic activity, which appears to be independent of the receptor-transactivating activity. This review focuses on the relevant features of recently reported synthetic retinoids, with particular reference to their therapeutic potential and current understanding of the mechanism of action. These agents are structurally heterogeneous compounds, including molecules closely related to natural retinoids and molecules with a retinoid-like structure (e.g., atypical retinoids) that include retinoic acid receptor (RAR) selective compounds or RAR antagonists. Promising agents of this class are adamantyl retinoids because of their apoptotic potency, in vivo antitumour activity and low toxicity. Activity of selected adamantyl retinoids (e.g., CD437, MX3350-1, ST1926) has been reported in models of various tumour types, including ovarian, breast, lung, head/neck squamous carcinoma and melanoma. The best in vivo antitumour efficacy was achieved by a protracted treatment. Orally available molecules (e.g., ST-1926) are the most suitable for this treatment schedule. Synthetic retinoids have shown synergistic interaction in combination with a variety of antitumour agents used in clinical therapy. This evidence is expected to expand the therapeutic options for clinical use of retinoids.