Sunday, September 25, 2011

Androgens As Therapy For Androgen Receptor Positive Castration Resistant Prostate Cancer

Based on the results from the researchers’ model, patients developing relapsed hormone-refractory prostate tumors after androgen ablation therapy should be biopsied for expression level of Androgen Receptor (AR) protein in tumors. Intermittent Androgen Deprivation (IAD) and/or administration of exogenous androgen at a concentration 2500-3500 ng/dl will benefit patients with AR-rich relapsed tumors by suppressing tumor growth, improving quality of life, and reducing risks for cardiovascular diseases and diabetes. Combined treatment of androgen ablation therapy with anti-androgen causes a rapid and irreversible selection of more aggressive advanced prostate cancer cells. Exogenous androgen treatment can cause regression of these tumors and a subgroup of these tumors will disappear. Androgen deprivation therapy alone may promote a slow adaptation to androgen ablation-resistance, thus shortening the period of androgen deprivation therapy may retard the diseases progression and reduce side effects. Aromatase inhibitors should be considered in combination with androgen treatment to prevent the conversion of testosterone to estradiol (E2) by aromatase to avoid potential cardiac toxicity. Since several clinical trials already confirmed that testosterone is a safe, feasible, and reasonably well-tolerated therapy for men with early hormone-refractory prostate cancer, we believe that manipulating androgen/AR signaling can be a potential therapy for AR-positive advanced prostate cancer.

Chuu CP, Kokontis JM, Hiipakka RA, et al. Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer. J Biomed Sci 2011;18:63.

Prostate cancer is the most frequently diagnosed non-cutaneous tumor of men in Western countries. While surgery is often successful for organ-confined prostate cancer, androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side-effects, including increased risk of cardiovascular diseases. Shortening the period of androgen ablation therapy may benefit prostate cancer patients. Intermittent Androgen Deprivation therapy improves quality of life, reduces toxicity and medical costs, and delays disease progression in some patients.

Cell culture and xenograft studies using androgen receptor (AR)-positive castration-resistant human prostate cancers cells (LNCaP, ARCaP, and PC-3 cells over-expressing AR) suggest that androgens may suppress the growth of AR-rich prostate cancer cells. Androgens cause growth inhibition and G1 cell cycle arrest in these cells by regulating c-Myc, Skp2, and p27Kip via AR. Higher dosages of testosterone cause greater growth inhibition of relapsed tumors. Manipulating androgen/AR signaling may therefore be a potential therapy for AR-positive advanced prostate cancer.