Proliferation- and apoptosis-associated factors in advanced prostatic carcinomas before and after androgen deprivation therapy: prognostic significance of p21/WAF1/CIP1 expression

The molecular mechanisms leading to androgen-independent growth in prostate cancer (PC) are poorly understood. Androgen deprivation therapy (ADT) resu lts physiologically in a decrease in proliferation and an increase in progr ammed cell death (PCD)/apoptosis. The aim of our study was to get more insi ght into these processes in prostatic carcinomas before and after ADT. For this purpose; immunohistologic staining for the androgen receptor (AR) mole cule, the Ki-67 antigen, the bcl-2 oncoprotein, the p53 protein and its phy siologic effector, p21/WAF1, was performed on archival material. PCD was vi sualized by enzymatic detection of DNA fragmentation. Specimens from 69 PC patients after ADT were studied in correlation to histopathology and progno sis. In 42 cases, corresponding tumour tissue from the untreated primary tu mours could be analysed comparatively. Before ADT, histologic grade was ass ociated with Ki-67 index (P < 0.0001, Spearman correlation) and PCD rate(P < 0.05, Spearman correlation). Ki-67 index correlated with PCD rate (P < 0. 05, Spearman correlation) and p21/WAF1 expression (P < 0.01, Fisher's exact test). p21/WAF1 expression was the only statistically significant prognost ic factor for shorter survival (P < 0.002, log-rank test). All p21/WAF1-pos itive cases showed high Ki-67 index and high histologic grade. After ADT, l oss of AR expression was associated with high Ki-67 index, whereas histolog ic signs of regression correlated negatively with Ki-67 index (P < 0.001, P earson chi(2) test). p21/WAF1 expression increased significantly (P < 0.02, McNemar test) and correlated with p53 accumulation (P < 0.0001, Pearson ch i(2) test). Most significant prognostic parameter after conventional ADT wa s high-rate p21/WAF1 expression (> 50% of tumour cells; P < 0.00001, log-ra nk test). This study demonstrates that p21/WAF1 overexpression before and a fter ADT characterizes a subgroup of advanced PC with paradoxically high pr oliferation rate and significantly worse clinical outcome. This finding mig ht be clinically useful for planning therapy in these patients.