Antiandrogens in prostate cancer

Antiandrogens competitively inhibit ligand binding to the androgen receptor (AR), and are used therapeutically in prostate cancer patients. The AR fun ctions as a ligand dependent transcription factor that transduces androgen binding into increased transcription of androgen dependent genes. AR blocka de induces programmed cell death in the vast majority of malignant and beni gn prostate cancer cells that have not previously been exposed to androgen ablation. The antiandrogens are divided structurally into the steroidal and non stero idal agents. The biological effects of the steroidal versus nonsteroidal ag ents are distinguished by differences in their effects on serum testosteron e levels, and by their activity at receptors other than the androgen recept or. There is extensive clinical experience in the palliative and curative t herapy of prostate cancer using antiandrogens as monotherapy or antiandroge ns in combination with luteinizing hormone agonists or surgical castration. Prolonged therapy with antiandrogens selects for mutations in the AR that c hange the AR ligand specificity and permits stimulation by ligands that are usually inhibitory. These mutations give insight into one of the means by which prostate cancer progresses despite antiandrogen therapy, and also hel ps to explain the antiandrogen withdrawal syndrome. Areas of active research that may affect the future use of antiandrogens in clude the ongoing evaluation of antiandrogens in combination with 5 alpha r eductase inhibitors to achieve AR blockade without inducing castrate testos terone levels. There is also interest in developing selective androgen rece ptor modulators (SARM) that can achieve AR blockade without causing the inc reased testosterone levels produced by the nonsteroidal antiandrogens curre ntly in use.