Antagonistic interaction between bicalutamide™ (Casodex®) and radiation in androgen-positive prostate cancer LNCaP cells

• Published in: The Prostate 2010-03, Vol.70 (4), p.401-411
• Main Authors: Quéro, Laurent, Giocanti, Nicole, Hennequin, Christophe, Favaudon, Vincent
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenocarcinoma - therapy; Androgen Antagonists - pharmacology; Anilides - pharmacology; antagonism; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - radiation effects; association; bicalutamide; Biological and medical sciences; Casodex; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - radiation effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; G1 Phase - drug effects; G1 Phase - radiation effects; Gynecology. Andrology. Obstetrics; Humans; Male; Male genital diseases; Medical sciences; Neoadjuvant Therapy; Nephrology. Urinary tract diseases; Nitriles - pharmacology; prostate; Prostate-Specific Antigen - metabolism; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms - therapy; radiotherapy; Radiotherapy, Adjuvant; Receptors, Androgen - metabolism; S Phase - drug effects; S Phase - radiation effects; Time Factors; Tosyl Compounds - pharmacology; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.21074

BACKGROUND Bicalutamide™ (Casodex®) reportedly improves high‐risk prostate cancer survival as an adjuvant treatment following radiotherapy. However, biological data for the interaction between bicalutamide and ionizing radiation in concomitant association are lacking. METHODS To explore this issue, androgen‐dependent (LNCaP) and ‐independent (DU145) human prostate cancer cells were exposed for 48 hr to 20, 40, or 80 µM bicalutamide introduced before (neoadjuvant), during (concomitant), or following (adjuvant) radiation. Growth inhibition and cytotoxicity, cell cycle distribution and expression of the prostate serum antigen (PSA) and androgen receptor (AR), were measured as endpoints. RESULTS Bicalutamide‐induced cytotoxic and cytostatic effects were found to be correlated with a marked G1 phase arrest and S phase depression. The drug down‐regulated PSA and AR proteins and psa mRNA in LNCaP cells. However, transient up‐regulation of the expression of ar mRNA was observed in the presence of 40 µM drug. DU145 cells did not express PSA and proved to be comparatively resistant to the drug from both cytostatic and cytotoxic effects. Bicalutamide dose‐dependently induced a significant decrease of radiation susceptibility among drug survivors in LNCaP cells, whilst the interaction appeared to be additive in DU145 cells. CONCLUSIONS The antagonistic radiation–drug interaction observed in LNCaP cells is of significance in relation to combined radiotherapy–bicalutamide treatments directed against tumors expressing the AR. The results suggest that bicalutamide is amenable to combined schedule with radiotherapy provided the drug and radiation are not given in close temporal proximity. Prostate 70: 401–411, 2010. © 2009 Wiley‐Liss, Inc.