© 2 0 0 6 B J U I N T E R N A T I O N A L | 9 7 , 6 9 1 – 6 9 7 | doi:10.1111/j.1464-410X.2006.05974.x 6 9 1 Original Article RALOXIFENE AND ANDROGEN-INDEPENDENT PROSTATE CANCER SHAZER et al. Raloxifene, an oestrogen-recepto b - targeted therapy, inhibits androg independent prostate cancer grow results from preclinical studies an pilot phase II clinical trial RONALD L. SHAZER, ANJALI JAIN, ANNA V. GALKIN, NADYA CINMAN, KOO N. NGUYEN, RONALD B. NATALE*, MITCHELL GROSS, LELAND GRE LEON I. BENDER‡, STUART HOLDEN, LESLIE KAPLAN§ and DAVID B. AGU Louis Warschaw Prostate Cancer Center, Cedars-Sinai Medical Center and *Cedars-Sina Comprehensive Cancer Center, †Tower Hematology Oncology Medical Group, ‡Leon I. B Urology, and §Pacific Urology, Los Angeles, CA, USA Accepted for publication 23 September 2005 OBJECTIVES To determine, in preclinical in vivo animal and in clinical studies, whether raloxifene (a selective oestrogen-receptor (ER) modulator that targets ER- β and induces apoptosis in vitro in androgen- independent prostate cancer, AIPC cells) affects prostate cell differentiation, proliferation and carcinogenesis, and in the pilot phase II clinical trial, the response rate and duration of patients with AIPC treated with a daily oral dose of raloxifene. PATIENTS, MATERIALS AND METHODS Tumour proliferation rate in response to raloxifene treatment, and molecular markers of cell cycle and apoptosis, were evaluated in established ER- β-positive androgen-dependent (AD) CWR22 and AI CWRSA9 human xenograft prostate cancer models. Twenty-one patients with AIPC and evidence of disease progression were enrolled into the clinical trial and given daily oral raloxifene. RESULTS There was significant growth inhibition by raloxifene in the ADPC and AIPC xenograft models (CWR22 68%, P < 0.010; CWRSA9 64%, P < 0.001), with no tumour regression. There was evidence of G1 arrest by increased p27kip1 expression in the raloxifene-treated group. Eighteen patients comprised the efficacy analysis, as three withdrew before the first evaluation. At the first evaluation, five men had stable disease and continued on the study for a median of five cycles. The longest response was 17 cycles. Drug related toxicity was minimal. CONCLUSION Raloxifene has activity in xenograft models, slowing disease progression. This translated to possible disease stabilization in patients with AIPC. Further studies are warranted. KEYWORDS selective oestrogen receptor modulator, raloxifene, prostate cancer, ER- β , androgen independence Authors from the USA present preclinical studies and the results of a pilot phase II clinical trial into the use of raloxifene, a therapy targeted as the oestrogen receptor- b , which may be important in prostate cell differentiation, proliferation and carcinogenesis. The authors found that it slowed disease progression in xenograft models, and might perhaps stabilize disease in patients with androgen-insensitive prostate cancer. Authors from Norway present a national population-based cohort study to determine the possible greater occurrence than might have been expected of multiple malignancies in patients with RCC. They found that, indeed, such patients have a significantly greater risk of developing other subsequent primary malignancies, an important issue relating to follow-up.