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

Abstract

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 microM 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 microM 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.