Metabolism of free and complexed prostate - specific antigen and their utility for diagnosis and prognosis of prostate cancer

Abstract: Prostate-specific antigen (PSA) is a glycoprotein produced by the prostate gland. It occurs in several molecular forms in the blood and assays have been developed to measure free PSA and PSA in complex with alpha-1-antichymotrypsin (PSA-ACT). Higher proportions of free PSA (PSA-F/T) in blood are found in subjects with benign prostatic hyperplasia (BPH) as compared to cancer patients. Utilizing immunocytochemistry and in situ hybridization we demonstrated production of PSA and ACT in normal and malignant prostatic tissue. In areas with BPH however, only PSA was detected, which may be linked to the differences in proportions of PSA-F/T found in blood from patients with cancer compared to subjects with BPH. Comparing selective measurements of the PSA forms and their ratios by receiver operating characteristics showed that PSA-F/T best discriminated cancer from BPH in patients with normal or slightly elevated PSA levels. After removal of the prostate the elimination of free PSA was bi-exponential with an initial, rapid re-distribution phase followed by a terminal phase with a half-life of 14 hours. PSA-ACT was eliminated slowly and non-exponentially with a mean rate of 0.8 ng/mL/day indicating a capacity-limited process. In hormonally deprived patients with high pre-treatment PSA concentrations, both free PSA and PSA-ACT were eliminated exponentially with mean half-lives of 10 and 13 days respectively. In 66 prostate cancer patients followed until death or for a minimum of nine years, univariate analysis showed that all PSA forms, but not their ratios, as well as tumour grade, local and distant stage gave prognostic information on cancer survival. In a multivariate analysis with step-wise entering of factors only grade, distant stage and the PSA-F/PSA-ACT ratio provided prognostic information.