Cellular changes in prostate cancer cells induced by intermittent androgen suppression

Objectives: This study used tumour specimens from a clinical trial on intermittent androgen suppression (lAS) to study the effects of castration on tissue morphology, cell proliferation, apoptosis, and the expression of androgen receptor (AR). Methods: A total of 113 representative needle biopsy specimens were available from 29 patients for evaluation of the Gleason score as well as Ki-67, cleaved caspase-3, and AR immunostaining. Results: At 6 mo from the beginning of the first androgen withdrawal, cell proliferation activity was significantly (p = 0.002) reduced, whereas no effect on apoptosis was found. A nonsignificant trend to an increase in Gleason score after castration was found. Subsequent cycles of withdrawals had no significant effect on any of the measured parameters. The Gleason score, proliferation activity, and apoptosis rate showed only heterogeneous, nonsignificant changes after the first progression. Strong nuclear AR staining was evident in all cancer specimens. Conclusions: The findings suggest that the long-term (months) effect of androgen withdrawal on tumour growth is due to the inhibition of proliferation. Because the tumours seem to become resistant to castration at the first cycle of treatment withheld, it is possible that IAS does not postpone the emergence of ablation-resistant tumours. There was no consistent sign of increased proliferation or Gleason score during the treatment, suggesting that the biologic aggressiveness of a particular tumour is defined already at an early stage of disease. The constant nuclear expression of AR in cancer cells indicates that the AR signalling remains active despite of the androgen withdrawal. (c) 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.