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1-Antichymotrypsin Is the Major Form of Prostate-specific Antigen in Serum of Patients with Prostatic Cancer: Assay of the Complex Improves Clinical Sensitivity for Cancer1
Clinical Laboratory, Departments I and II of Obstetrics and Gynecology [U-H. S., J. L., H. A.] and II Department of Surgery [S. R., K. T., O. A.], Helsinki University Central Hospital, SF-00290 Helsinki, Finland
We have studied the forms of prostate-specific antigen (PSA) in serum of patients with prostatic cancer and benign prostatic hyperplasia. Fractionation of serum by gel filtration and assay of the fractions for PSA showed that a considerable part of the PSA immunoreactivity in serum consisted of complexes that were larger than PSA. The complexes were assayed by time-resolved immunofluorometric assays based on an antibody against PSA on the solid phase and europium-labeled antibodies against various protease inhibitors as indicator antibodies. In addition to its monomeric form, PSA was found to occur in complex with 
1-antichymotrypsin. The proportion of the 1-antichymotrypsin complex was a major form of PSA and it increased with increasing PSA concentrations, being over 85% at PSA levels exceeding 1000 µg/liter. A complex with 1-protease inhibitor was also observed in serum of patients with prostatic cancer and very high levels of PSA. Complexes with 2-macroglobulin and inter--trypsin inhibitor were detected, but their concentrations were low and similar in sera of cancer patients, normal men, and normal women, suggesting that they were not prostate derived. Commercial immunoradiometric assays for PSA were found to measure free PSA and its complexes with 1-antichymotrypsin but not the complexes with 2-macroglobulin and inter--trypsin inhibitor. The proportion of the PSA-1-antichymotrypsin complex was higher in patients with prostatic cancer than in those with benign hyperplasia. Therefore, assay of the complex had a higher sensitivity for cancer than assay of total PSA immunoreactivity.
1 This work was supported by grants from The Academy of Finland, Sigrid Jusétius Foundation, The Finnish Cancer Institute, The Finnish Social Insurance Institution, and The Finska Läkaresällskapet.
2 To whom requests for reprints should be addressed.
Received 1/24/90. Accepted 10/15/90.
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J. Peter, C. Unverzagt, and W. Hoesel Analysis of Free Prostate-specific Antigen (PSA) after Chemical Release from the Complex with {alpha}1-Antichymotrypsin (PSA-ACT) Clin. Chem., April 1, 2000; 46(4): 474 - 482. [Abstract] [Full Text] [PDF]
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S. D. Mikolajczyk, L. S. Millar, T. J. Wang, H. G. Rittenhouse, L. S. Marks, W. Song, T. M. Wheeler, and K. M. Slawin A Precursor Form of Prostate-specific Antigen Is More Highly Elevated in Prostate Cancer Compared with Benign Transition Zone Prostate Tissue Cancer Res., February 1, 2000; 60(3): 756 - 759. [Abstract] [Full Text]
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C. Becker, T. Piironen, J. Kiviniemi, H. Lilja, and K. Pettersson Sensitive and Specific Immunodetection of Human Glandular Kallikrein 2 in Serum Clin. Chem., February 1, 2000; 46(2): 198 - 206. [Abstract] [Full Text] [PDF]
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D. K. Ornstein, C. Englert, J. W. Gillespie, C. P. Paweletz, W. M. Linehan, M. R. Emmert-Buck, and E. F. Petricoin III Characterization of Intracellular Prostate-specific Antigen from Laser Capture Microdissected Benign and Malignant Prostatic Epithelium Clin. Cancer Res., February 1, 2000; 6(2): 353 - 356. [Abstract] [Full Text]
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M. H. Black, M. Giai, R. Ponzone, P. Sismondi, H. Yu, and E. P. Diamandis Serum Total and Free Prostate-specific Antigen for Breast Cancer Diagnosis in Women Clin. Cancer Res., February 1, 2000; 6(2): 467 - 473. [Abstract] [Full Text]
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T. Tanaka, T. Isono, T. Yoshiki, T. Yuasa, and Y. Okada A Novel Form of Prostate-specific Antigen Transcript Produced by Alternative Splicing Cancer Res., January 1, 2000; 60(1): 56 - 59. [Abstract] [Full Text]
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K. Jung, B. Brux, M. Lein, B. Rudolph, G. Kristiansen, S. Hauptmann, D. Schnorr, S. A. Loening, and P. Sinha Molecular Forms of Prostate-specific Antigen in Malignant and Benign Prostatic Tissue: Biochemical and Diagnostic Implications Clin. Chem., January 1, 2000; 46(1): 47 - 54. [Abstract] [Full Text] [PDF]
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K. Jung, U. Elgeti, M. Lein, B. Brux, P. Sinha, B. Rudolph, S. Hauptmann, D. Schnorr, and S. A. Loening Ratio of Free or Complexed Prostate-specific Antigen (PSA) to Total PSA: Which Ratio Improves Differentiation between Benign Prostatic Hyperplasia and Prostate Cancer? Clin. Chem., January 1, 2000; 46(1): 55 - 62. [Abstract] [Full Text] [PDF]
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R. Stege, M. Grande, K. Carlström, B. Tribukait, and A. Pousette Prognostic Significance of Tissue Prostate-specific Antigen in Endocrine-treated Prostate Carcinomas Clin. Cancer Res., January 1, 2000; 6(1): 160 - 165. [Abstract] [Full Text]
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A. Magklara, A. Scorilas, W. J. Catalona, and E. P. Diamandis The Combination of Human Glandular Kallikrein and Free Prostate-specific Antigen (PSA) Enhances Discrimination Between Prostate Cancer and Benign Prostatic Hyperplasia in Patients with Moderately Increased Total PSA Clin. Chem., November 1, 1999; 45(11): 1960 - 1966. [Abstract] [Full Text] [PDF]
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D. W. Chan, C. A. Kelley, T. L. Ratliff, D. D'Agostino, J. Ritchey, D. J. Lamb, J. Beck, N. Lott, M. H. Wener, P. Daum, et al. Analytical and Clinical Performance Characteristics of Hybritech's Tandem-R free PSA Assay during a Large Multicenter Clinical Trial to Determine the Clinical Utility of Percentage of Free Prostate-specific Antigen Clin. Chem., October 1, 1999; 45(10): 1863 - 1865. [Full Text] [PDF]
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M. P. Fox, A. A. Reilly, and E. Schneider Effect of the Ratio of Free to Total Prostate-specific Antigen on Interassay Variability in Proficiency Test Samples Clin. Chem., August 1, 1999; 45(8): 1181 - 1189. [Abstract] [Full Text] [PDF]
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A. Virtanen, M. Gomari, and R. Kranse Estimation of Prostate Cancer Probability by Logistic Regression: Free and Total Prostate-specific Antigen, Digital Rectal Examination, and Heredity Are Significant Variables Clin. Chem., July 1, 1999; 45(7): 987 - 994. [Abstract] [Full Text] [PDF]
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U.-H. Stenman New Ultrasensitive Assays Facilitate Studies on the Role of Human Glandular Kallikrein (hK2) as a Marker for Prostatic Disease Clin. Chem., June 1, 1999; 45(6): 753 - 754. [Full Text] [PDF]
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D. W. Chan and L. J. Sokoll Prostate-specific Antigen: Advances and Challenges Clin. Chem., June 1, 1999; 45(6): 755 - 756. [Full Text] [PDF]
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M. H. Black, A. Magklara, C. V. Obiezu, D. N. Melegos, and E. P. Diamandis Development of an Ultrasensitive Immunoassay for Human Glandular Kallikrein with No Cross-Reactivity from Prostate-specific Antigen Clin. Chem., June 1, 1999; 45(6): 790 - 799. [Abstract] [Full Text] [PDF]
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W.-M. Zhang, P. Finne, J. Leinonen, S. Vesalainen, S. Nordling, and U.-H. Stenman Measurement of the Complex between Prostate-specific Antigen and {alpha}1-Protease Inhibitor in Serum Clin. Chem., June 1, 1999; 45(6): 814 - 821. [Abstract] [Full Text] [PDF]
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S. Michel, G. Deleage, J.-P. Charrier, J. Passagot, N. Battail-Poirot, G. Sibai, M. Jolivet, and C. Jolivet-Reynaud Anti-Free Prostate-specific Antigen Monoclonal Antibody Epitopes Defined by Mimotopes and Molecular Modeling Clin. Chem., May 1, 1999; 45(5): 638 - 650. [Abstract] [Full Text] [PDF]
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H. Nagasaki, M. Watanabe, N. Komatsu, T. Kaneko, J. Y. Dube, T. Kajita, Y. Saitoh, and Y. Ohta Epitope Analysis of a Prostate-specific Antigen (PSA) C-Terminal-specific Monoclonal Antibody and New Aspects for the Discrepancy between Equimolar and Skewed PSA Assays Clin. Chem., April 1, 1999; 45(4): 486 - 496. [Abstract] [Full Text] [PDF]
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M. H. Black, C. L. Grass, J. Leinonen, U.-H. Stenman, and E. P. Diamandis Characterization of Monoclonal Antibodies for Prostate-specific Antigen and Development of Highly Sensitive Free Prostate-specific Antigen Assays Clin. Chem., March 1, 1999; 45(3): 347 - 354. [Abstract] [Full Text] [PDF]
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K. Jung, B. Brux, A. Knabich, M. Lein, P. Sinha, D. Schnorr, and S. A. Loening A Gap Between Total Prostate-specific Antigen and the Sum of Free Prostate-specific Antigen Plus {alpha}1-Antichymotrypsin-Prostate-specific Antigen in Patients with Prostate Carcinoma but not in Those with Benign Prostate Hyperplasia Clin. Chem., March 1, 1999; 45(3): 422 - 424. [Full Text] [PDF]
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M. Gion, R. Mione, P. Barioli, M. Barichello, F. Zattoni, T. Prayer-Galetti, M. Plebani, G. Aimo, C. Terrone, F. Manferrari, et al. Percent free prostate-specific antigen in assessing the probability of prostate cancer under optimal analytical conditions Clin. Chem., December 1, 1998; 44(12): 2462 - 2470. [Abstract] [Full Text] [PDF]
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W.-M. Zhang, P. Finne, J. Leinonen, S. Vesalainen, S. Nordling, S. Rannikko, and U.-H. Stenman Characterization and immunological determination of the complex between prostate-specific antigen and {alpha}2-macroglobulin Clin. Chem., December 1, 1998; 44(12): 2471 - 2479. [Abstract] [Full Text] [PDF]
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C. Lopez-Otin and E. P. Diamandis Breast and Prostate Cancer: An Analysis of Common Epidemiological, Genetic, and Biochemical Features Endocr. Rev., August 1, 1998; 19(4): 365 - 396. [Abstract] [Full Text] [PDF]
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C. D. Cheli, M. Marcus, J. Levine, Z. Zhou, P. H. Anderson, D. D. Bankson, J. Bock, S. Bodin, C. Eisen, M. Senior, et al. Variation in the Quantitation of Prostate-specific Antigen in Reference Material: Differences in Commercial Immunoassays, Clin. Chem., July 1, 1998; 44(7): 1551 - 1553. [Full Text] [PDF]
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W. J. Allard, Z. Zhou, and K. K. Yeung Novel immunoassay for the measurement of complexed prostate-specific antigen in serum Clin. Chem., June 1, 1998; 44(6): 1216 - 1223. [Abstract] [Full Text] [PDF]
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W. J. Catalona, A. W. Partin, K. M. Slawin, M. K. Brawer, R. C. Flanigan, A. Patel, J. P. Richie, J. B. deKernion, P. C. Walsh, P. T. Scardino, et al. Use of the Percentage of Free Prostate-Specific Antigen to Enhance Differentiation of Prostate Cancer From Benign Prostatic Disease: A Prospective Multicenter Clinical Trial JAMA, May 20, 1998; 279(19): 1542 - 1547. [Abstract] [Full Text] [PDF]
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K. Jung, P. von Klinggraff, B. Brux, P. Sinha, D. Schnorr, and S. A. Loening Preanalytical Determinants of Total and Free Prostate-Specific Antigen and Their Ratio: Blood Collection and Storage Conditions Clin. Chem., March 1, 1998; 44(3): 685 - 688. [Full Text] [PDF]
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R. Junker, B. Brandt, C. Zechel, and G. Assmann Comparison of prostate-specific antigen (PSA) measured by four combinations of free PSA and total PSA assays Clin. Chem., September 1, 1997; 43(9): 1588 - 1594. [Abstract] [Full Text] [PDF]
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T. K. Takayama, K. Fujikawa, and E. W. Davie Characterization of the Precursor of Prostate-specific Antigen. ACTIVATION BY TRYPSIN AND BY HUMAN GLANDULAR KALLIKREIN J. Biol. Chem., August 22, 1997; 272(34): 21582 - 21588. [Abstract] [Full Text] [PDF]
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D. L. Woodrum, C. M. French, T. M. Hill, S. J. Roman, H. L. Slatore, J. L. Shaffer, L. G. York, K. L. Eure, K. G. Loveland, G. H. Gasior, et al. Analytical performance of the Tandem(R)-R free PSA immunoassay measuring free prostate-specific antigen Clin. Chem., July 1, 1997; 43(7): 1203 - 1208. [Abstract] [Full Text] [PDF]
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W. J. Catalona, D. S. Smith, and D. K. Ornstein Prostate Cancer Detection in Men With Serum PSA Concentrations of 2.6 to 4.0 ng/mL and Benign Prostate Examination: Enhancement of Specificity With Free PSA Measurements JAMA, May 14, 1997; 277(18): 1452 - 1455. [Abstract] [PDF]
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A. B. Blase, R. L. Sokoloff, and K. M. Smith Five PSA Methods Compared by Assaying Samples with Defined PSA Ratios, Clin. Chem., May 1, 1997; 43(5): 843 - 845. [Full Text]
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