Progress in understanding androgen-independent prostate cancer (AIPC): a review of potential endocrine-mediated mechanisms.

This review is triggered by recent developments that offer new explanations for the mechanism of progression of prostate cancer to androgen independence. Established and hypothetical mechanisms, which have been described in the past, are put into perspective with recent progress in the field. A total of seven mechanisms can be identified that relate to progression to androgen independence. Five of those are dependent on the androgen receptor, which is present or over-expressed in androgen-independent prostate cancer tissue. Probably due to selective pressure, AIPC cells have the capability to escape from the effect of castration and antiandrogens; exclusion of the androgen receptor activity by inhibition of dimerisation or inhibition of DNA binding seem to be the logical next steps. Although androgen levels and androgen synthesis are suppressed in prostatic tissues during the phase of response to endocrine treatment, androgen levels and, specifically, 5-alpha-dihydrotestosterone (DHT) were elevated in tissues derived from metastases of AIPC. In addition, all enzymes needed to synthesise androgens from the level of pregnenolone on are present or over-expressed in such tissue. This offers new potential for treatment.