A new generation of retinoid drugs for the treatment of dermatological diseases

Abstract

Dermatological diseases such as acne, psoriasis, and various skin cancers affect approximately 24 million people in the US (17 million acne, 6.4 million psoriasis and 0.7 million skin cancer). In many cases, particularly for acne and psoriasis, these diseases have exhibited favourable responses to single agent or adjuvant retinoid therapy. When administered as both chemotherapeutic and chemopreventive agents, they offer a viable alternative to classical cancer chemotherapy. Although retinoid treatment has shown considerable promise, certain side-effects have limited their utility for chronic administration. Accordingly, there is considerable interest in developing novel retinoids that exhibit improvements in the side-effect profile, particularly for diseases that require chronic administration. Retinoids are potent biological modulators that exert their effects through intracellular receptors (retinoic acid receptors [RARs] and retinoid X receptors [RXRs]) where they regulate cellular proliferation, differentiation and programmed cell death. Currently, using a combination of molecular biology and synthetic chemistry, efforts are underway to fully characterise the biological role of individual retinoid receptor subtypes. Using receptor-selective retinoids, recent discoveries have assisted in clarifying the mechanism and biological function of retinoids and their receptors. It now appears that the RARs are implicated in the regulation of cellular proliferation and differentiation, whereas the RXRs function as modulators of programmed cell death or apoptosis. This suggests that diseases that are associated with abnormal proliferation and/or differentiation may be treatable with RAR active compounds. In fact, the data are supported by successful treatment of psoriasis, epithelial cancer and leukaemia with retinoids that preferentially activate the RARs. In contrast, retinoids that preferentially activate RXRs may be desirable for treatment of diseases for which enhancement of apoptosis is required. For example, they are potentially useful for treatment of cutaneous T-cell lymphoma and as chemopreventive agents [1]. The mechanisms of action of these RXR mediated effects are under investigation. Finally, certain receptor subtypes are implicated in retinoid side-effects. For example, it has become increasingly evident that side-effects such as triglyceridaemia [2] and teratogenesis [3,4] can be correlated to activation of the RARs and not the RXR. These findings offer opportunities for developing a new generation of retinoids which exhibit improved therapeutic indices. Recently, novel treatment strategies have evolved including the application of receptor-selective synthetic retinoids, combination therapies with other hormones or chemotherapeutic agents, and novel formulations. This has resulted in a new generation of retinoids and retinoid treatments which are in clinical development and which exhibit improvements in the therapeutic index.