Prostate-specific antigen: advances and challenges.

نویسندگان

  • D W Chan
  • L J Sokoll
چکیده

In the quarter-century since its discovery (1 ), prostatespecific antigen (PSA) has been recognized as the most effective tumor marker for prostate cancer and has unquestionably played an important role in the diagnosis and clinical management of this disease. Prostate cancer remains the leading cancer site in men, with 179 300 new cancer cases estimated by the American Cancer Society for 1999, a slight decrease from the 1998 estimate of 184 500 cases (2 ). In addition to decreasing cancer cases, deaths from prostate cancer and cancer in general are declining, and prostate cancer survival rates are increasing (2 ). The incidence of prostate cancer has changed dramatically in the PSA era following the introduction of the first generation of PSA assays in the mid-1980s. Prostate cancer incidence increased 84% between 1987 and 1992 and then declined 46% between 1992 and 1994. This pattern has been attributed, in part, to increased cancer detection as a result of PSA testing with subsequent earlier diagnoses (3 ). Early detection of cancer affords a greater chance of detecting cancers at an early stage, when cancer is confined to the prostate and curative treatment is possible. Although PSA is considered an effective tumor marker and is for all intents and purposes organ specific, it is not cancer specific. There is considerable overlap in PSA concentrations in men with prostate cancer and men with benign prostate diseases, particularly in the range of 4–10 mg/L. This range has thus been termed the diagnostic gray zone. Several approaches have been proposed and investigated to improve the diagnostic accuracy of PSA, including age-specific reference ranges, PSA density, PSA velocity, neural network-derived indexes, and the molecular forms of PSA (4 ). Use of the molecular forms, primarily focusing on free PSA and PSA bound to a1antichymotrypsin (ACT), has shown the most promise. In an article in a previous issue of Clinical Chemistry (5 ) and one in the present issue (6 ), Zhang and co-workers from the laboratory of Dr. Ulf-Håkan Stenman describe the formation of PSA complexes with a2-macroglobulin (A2M) and a1-protease inhibitor (API); these articles are significant for their contributions in furthering the attempt to improve the clinical utility of PSA as well as the understanding of the biology of PSA. PSA, synthesized in the ductal epithelium of the prostate, is a member of the human kallikrein gene family and functions as a serine protease. PSA has been observed to form complexes with ACT, A2M, API, and protein C inhibitor in vitro (7 ), with the majority of PSA in serum complexed to ACT and A2M. In the early 1990s, Lilja et al. (8 ) and Stenman et al. (9 ) discovered that in serum, the majority of PSA (80–90%) is bound to protease inhibitors, whereas a small proportion (10–20%) is in the free form. It was also discovered that men with prostate cancer and men without cancer may differ in the proportions of free PSA and PSA-ACT, with a higher percentage of PSA bound to ACT in men with cancer (9 ). Current total-PSA assays measure free PSA and available PSA complexes, primarily PSA-ACT. PSA-A2M is not immunoreactive because of the encapsulation of PSA by the A2M molecule. A second generation of assays for some of the molecular forms of PSA has been developed, based on the discoveries of Lilja et al. (8 ) and Stenman et al. (9 ). The development of assays for PSA-ACT has lagged behind that of assays for free PSA because of initial problems with nonspecific binding resulting from complexes between ACT and cathepsin G, the physiologic binding partner for ACT (10 ). Recently, however, an automated assay that measures all available PSA complexes (cPSA) was introduced by Bayer for the Immuno 1 analyzer. With the exception of PSA-ACT, little has been known about the concentrations of other circulating PSA complexes in prostate cancer and benign prostatic hyperplasia (BPH) until the recent work of Zhang and coworkers (5, 6), published in this journal. Although the binding of PSA and A2M has been studied in vitro, attempts to quantify PSA-A2M in serum with A2M antibody-based assays have been hampered by nonspecific binding of A2M (5, 11). Measurement of PSAA2M is also difficult because of the need to denature the A2M molecule to expose PSA epitopes. Sodium dodecyl sulfate has been investigated as a denaturing agent (12, 13), whereas high pH was used by Zhang et al. (5 ). In the assay described by Zhang et al. (5 ), serum PSA-A2M was measured using a PSA immunoassay after immunoadsorption of circulating immunoreactive PSA and denaturation of the remaining PSA-A2M complexes. Although the assay correlated with total-PSA concentrations in patient specimens, it underestimated PSA-A2M. Despite assay limitations, Zhang et al. were able show an increased median ratio of A2M-PSA to total PSA in BPH patients (19.5%) compared with prostate cancer patients (14.5%) when total-PSA concentrations were between 4 and 10 mg/L. This is in contrast to the behavior of PSA-ACT and may be explained by the mechanism of complex formation, observed in in vitro experiments, and by clearance (5 ). In the 4–10 mg/L diagnostic gray zone, the area under the ROC curve was greater for the percentage of PSA-A2M compared with total PSA. Unfortunately, the percentage of free PSA was not measured for comparison. Zhang et al. (6 ) have also characterized PSA-API serum complexes with the development of a time-resolved immunofluorometric assay. Using this assay, they were able to quantify the proportion of PSA-API present in the sera of patients with prostate cancer or BPH and determined that although the majority of patients with detectable concentrations had ,5% circulating PSA-API, a significant percentage of total PSA was attributable to PSA-API in 18% of patients with prostate cancer and 36% of patients with BPH. They additionally identified that free PSA, PSA-ACT, and PSA-API account for essentially all immunoreactive PSA. Differences among commercial asEditorial

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Age Specific Reference Levels of Serum Prostate-Specific Antigen, Prostate Volume and Prostate Specific Antigen Density in Healthy Iranian Men

Background: It is relevant to highlight that there is not a precise and perfect report on either 95 percentile value (upper limit of normal range) or on appropriate reference intervals for serum PSA in Iranian population. Objective: To determine age-specific reference ranges for serum prostate-specific antigen (PSA) concentration and PSA density (PSAD) and prostate volumes in a population of he...

متن کامل

Prostate specific antigen staining intensity in prostatic adenocarcinoma correlates with serum prostate specific antigen , Bandar Abbas, Iran

Introduction: Prostatic adenocarcinoma is one the most common malignances and the second cause of death in males due to cancer. Prostate Specific Antigen (PZSA) serum level is the first marker to screen such patients. We aimed in this study, to assess the intensity of prostatic adenocarcinoma tissue staining with PSA staining method. Methods: In this corss-sectional study, prostatic adenocarcin...

متن کامل

Age-Related Prostate Specific Antigen Reference Ranges in Healthy Northern Iranian Men

Background: Prostate cancer is the third most common malignancy in men worldwide. Despite being a helpful biomarker in prostate cancer, prostate specific antigen (PSA) is affected by different factors including age, lifestyle, geographical region and ethnicity. Objective: To determine the age specific serum PSA level among healthy Northern Iranian men and to compare the results of our study wit...

متن کامل

Preparation of prostate specific antigen standards for immunoradiometric assay

Background: Immunoradiometric assay is one of the most common and precise methods for determination of prostate specific antigen (PSA) in clinical laboratories. Usual use of human serum in routine assays has many disadvantages such as easy contamination and precipitation, instability and unavailability. Thus in order to avoid these problems the artificial matrix was used which acts sim...

متن کامل

What is the most appropriate test in detecting prostate cancer in patients with intermediate prostate specific antigen levels?

  Abstract   Background: Regarding the variety of tests present for detecting and also screening   prostate cancer and also bearing in mind the advantages and disadvantages of   these tests we decided to re-evaluate these tests (total prostate specific antigen and all   of its modifications) in detecting prostate cancer in men with intermediate serum   PSAlevels.   Methods: Following a cross se...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Clinical chemistry

دوره 45 6 Pt 1  شماره 

صفحات  -

تاریخ انتشار 1999