Research: CRAWFORD and colleagues,

Listed in Issue 23


CRAWFORD and colleagues, Division of Urology, University of Colorado Health Sciences Center, Denver USA write in their review (59 references) that understanding changes in prostate-specific antigen (PSA) may enable the differentiation between benign and malignant growth and the assessment of the use of PSA as a tool to monitor activity of chemoprevention agents.


PSA appears to be useful as a noninvasive marker of prostatic growth, but PSA changes should not be confused with a direct measure of tumour growth. PSA levels are a function of tumour volume but are also influenced by benign epithelium volume, grade of carcinoma (if any), inflammation, androgen levels, growth factors and extracellular matrix. PSA biological functions in the prostate and its secretions need to be more completely elucidated in order to more accurately understand prostate dynamics. Expression of PSA is androgen-regulated, being one of the most abundant prostate-derived proteins in the seminal fluid. Seminogelin, a major protein in seminal fluid, is cleaved by PSA, which is important to the liquifaction of semen. Less is known regarding other PSA substrates. Current studies demonstrate that cancer cases show an early slow linear PSA phase followed by a rapid exponential phase and that PSA levels start to increase exponentially approximately 7-9 years prior to diagnosis. The establishment of age-specific PSA reference ranges (ASRR) and of PSA velocity (PSAV) rates provide a baseline from which prediction models could measure malignant potential of a prostate cancer. Also, recent discoveries of different molecular forms of PSA in serum may permit a more accurate differentiation of benign and malignant growth as well as a more accurate measure of the efficacy of chemoprevention agents. If PSA doubling time is approximately 2.4-3.0 years and accurately reflects tumour doubling time, and if the average man has less than 0.5 ml of latent prostatic tumour tissue and the average stage T2 cancer is approximately 4 ml upon detection, then the available PSA data suggest that the 3 doublings necessary to change from 0.5-4.0 ml would take 7-12 years for a typical small volume tumour to reach the size of most state T2 tumours. That histologic cancers appear at much younger ages than previously known is disturbing and indicates that disease initiation may begin sooner than ever presumed likely. "Normal" PSA levels for men less than 40 years of age may need to be studied with an emphasis upon premalignant lesions, as younger men may represent the most appropriate population and premalignant lesions the most relevant clinical factor for prostate cancer chemoprevention studies and trials. Although the molecular composition and changes of PSA derived from premalignant lesions have yet to be elucidated, such investigations may lead to a more complete understanding of the possible progression or transformation of normal prostate cells to premalignancy and hence to cancer. High grade prostatic intraepithelial neoplasis (PIN) in and of itself does not account for elevated serum PSA levels; however subtle changes in the molecular dynamic of PSA may reveal the influence of androgens and the impact of chemopreventive agents.





Crawford ED et al. The role of prostate-specific antigen in the chemoprevention of prostate cancer. J Cell Biochem Suppl. 25: 149-55. 1996.


Currently some 50% of all men will experience prostate-related problems, either benign or malignant, during their lifetime. Most experts would agree that diagnostic accuracy and treatments available for prostate cancer have substantive room for improvement. The sooner the better.

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