Retinoids and their applications in clinic

Abstract

This review provides an overview of relevant aspects of retinoid physiology and molecular biology, and summarizes the current status of clinical investigations on the use of retinoid for the treatment of malignancies.The mechanism underlying the anticarcinogenic activity of retinoids appears to be associated with the ability of retinoids to modulate the growth and induce differentiation, and apoptosis of normal, premalignant, and malignant cellsin vitro andin vivo.Retinoid effects seem to be resulted from changes in gene expression mediated via specific nuclear receptors (termed retinoic acid receptors, RAR-α, -β and -γ). Chromosome translocations play an important role in APL pathogenesis. In the classical translocation, RAR a gene is fused with PML gene to form PML-RAR a chimeric gene, which is expressed in over 95% of the APL patients with t (15; 17) (q22; q21). Therefore, PML-RAR a fusion gene is the molecular marker of APL. ATRA can induce relocalization of the PML and restore the normal structure of POD. Furthermore, it could cause a degradation of PML-RAR α.In addition to the very high clinical response rate for APL patients treated with ATRA, clinical responses have been observed for patients with myelodysplastic syndrome, cutaneous T-cell lymphoma and skin cancers. Applications of retinoids are reviewed in different malignancies: including skin cancer, head and neck carcinoma, neuroblastoma, lung cancer, breast cancer, prostate cancer, bladder cancer and ovarian cancerin vivo andin vitro studies. The results indicate that retinoids are potentially useful agents for cancer prevention.RA combined with IFNs or RA combined with G-CSF has synergistic effect in inducing differentiation of cell growth. From current clinical results at least four leads are expected to impact on clinical development of retinoids in future: (1) development of retinoid receptor-selective agents; (2) investigation on cross-talk among members of the steroid superfamily; (3) strategies for attaining sufficient tissue levels of retinoids; (4) combined use with other differentiation or chemotherapeutic agents.