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Prostate-Specific Antigen in Benign Prostatic Hyperplasia and Prostate Cancer

M.J. Heeb, F. Espana,* Y. Montejano

* La Fe University Hospital, Valencia, Spain

Serum prostate-specific antigen (PSA) is a valuable marker for prostate cancer. However, patients with benign prostatic hyperplasia also have increased PSA levels, and many patients with localized prostate cancer have normal PSA levels. Unnecessary biopsies are performed, and improved tests are needed. In blood, PSA circulates free and in complex with ₁-antichymotrypsin (₁ACT). Determination of the ratio of free PSA (F) or PSA-₁ACT (C) to total PSA (T) enhances the discrimination between prostate cancer and benign hyperplasia.

Determining the C/T ratio instead of the F/T ratio is advantageous in samples with low concentrations of total PSA in which only a small fraction of PSA is in the free form. We showed that in patients with prostate tumors and concentrations of total PSA less than 15 ng/ml, using a cutoff of 0.80 for the C/T ratio instead of a concentration of total PSA of 4 ng/ml increased the specificity for detection of prostate cancer from 38% to 79% without decreasing sensitivity (82%). The C/T ratio in patients with benign prostatic hyperplasia did not vary with age or with treatment as concentrations of total PSA do. In addition, the PSA-₁ACT complex is more stable in serum than is free PSA.

We compared C/T ratios obtained with our assays with F/T ratios obtained with a recently available commercial assay for free PSA. For these studies, we assayed serum and plasma samples from 170 consecutive patients who had biopsies of possible prostate tumors. We examined both serum and plasma samples because PSA forms may be more stable in plasma than in serum in which blood clotting occurred.

Receiver-operating characteristic curves were constructed for the total population of 170 samples and for the zones of total PSA concentrations of 2--20, 4--20, 2--10, and 4--10 ng/ml. For all groups, C/T ratios had higher specificity for detection of prostate cancer than did both F/T ratios and concentrations of total PSA, especially for sensitivity levels between 90% and 100%. Specificity was higher for plasma samples than for serum samples for all sensitivity values. The best results for C/T and F/T ratios were in samples with concentrations of total PSA of 2--10 ng/ml, the most useful range for early diagnosis of prostate cancer.

We also showed that PSA complexes rapidly with ₂-macroglobulin and that the complexes are present in patients' sera but are not detected by clinical assays. We developed an assay for the complex and are evaluating the ratio of PSA--₂-macroglobulin to total PSA in efforts to further improve the sensitivity and specificity for detection of prostate cancer. New studies also focus on the prognostic value of measurements of different forms of PSA, potentially as an aid in treatment selection in prostate cancer.

PUBLICATIONS

Fernández, J.A., Griffin, J.H., Chang, G.T.G., Stam, J., Reitsma, P.H., Bertina, R.M., Bouma, B.N. Involvement of amino acid residues 423-429 of human protein S in binding to C4b-binding protein. Blood Cells Mol. Dis. 24:101, 1998.

Hackeng, T.M., Yegneswaran, S., Dawson, P.E., Johnson, A.E., Kent, S.B.H., Griffin, J.H. Chemical synthesis of human protein S thrombin-sensitive module and first epidermal growth factor module. Biopolymers, in press.

Kojima, Y., Gale, A., Heeb, M.J., Hackeng, T.M., Griffin, J.H. Binding sites for blood coagulation factor Xa involving residues 311-325 in factor Va. J. Biol. Chem., in press.

Petäjä, J., Fernández, J.A., Fellman, V., Griffin, J.H. Upregulation of the anti-thrombotic protein C pathway at birth. Pediatr. Hematol. Oncol., in press.

Petäjä, J., Griffin, J.H. Activated protein C resistance: What have we learned now that the dust has settled? Ann. Med. 29:469, 1997.

Smiley, S.T., Boyer, S.N., Heeb, M.J., Griffin, J.H., Grusby, M.J. Protein S is inducible by interleukin 4 in T cells and inhibits lymphoid procoagulant activity. Proc. Natl. Acad. Sci. U.S.A. 94:11484, 1997.

Wang, L., Zoppe, M., Hackeng, T., Griffin, J.H., Lee, K.-F., Verma, I.M. A factor IX-deficient mouse model for hemophilia B gene therapy. Proc. Natl. Acad. Sci. U.S.A. 94:11563, 1997.