title: A truncated precursor form of prostate-specific antigen is a more specific serum marker of prostate cancer.
abstract: Prostate-specific antigen (PSA) is a widely used serum marker for prostate cancer (PCa) but has limited specificity for distinguishing early PCa from benign prostatic hyperplasia, because both PCa and benign prostatic hyperplasia release PSA into the serum. We have identified previously a truncated form of precursor PSA (pPSA) in prostate tumor extracts consisting of PSA with a serine-arginine pro leader peptide ([-2]pPSA) instead of the normally expressed 7 amino acid pro leader peptide. In the current study we developed monoclonal antibodies to detect [-2]pPSA and other isoforms of pPSA for Western blot analysis. PSA was immunoaffinity purified from 100 to 200 ml of serum from each of five men with biopsy-proven cancer and three biopsy-negative men, all with total PSA levels in the diagnostically relevant range near 10 ng/ml. The truncated [-2]pPSA was estimated to range from 25 to 95% of the free PSA in the five PCa samples but only 6-19% of the free PSA in the biopsy-negative men. Immunohistochemical studies showed positive staining for [-2]pPSA in PCa epithelium and that [-2]pPSA was enriched in cancer cell secretions. In vitro activation studies showed that human kallikrein 2 and trypsin readily activated full-length pPSA but were unable to activate [-2]pPSA to mature PSA. Thus, [-2]pPSA, once formed, is a stable but inactive isoform of PSA. Truncated [-2]pPSA may represent an important new diagnostic marker for the early detection of PCa.
authors.affiliation: Hybritech, Inc., San Diego, California 92121, USA. sdmikolajczyk@beckman.com
authors.forename: S D
authors.initials: SD
authors.lastname: Mikolajczyk
authors.forename: K M
authors.initials: KM
authors.lastname: Marker
authors.forename: L S
authors.initials: LS
authors.lastname: Millar
authors.forename: A
authors.initials: A
authors.lastname: Kumar
authors.forename: M S
authors.initials: MS
authors.lastname: Saedi
authors.forename: J K
authors.initials: JK
authors.lastname: Payne
authors.forename: C L
authors.initials: CL
authors.lastname: Evans
authors.forename: C L
authors.initials: CL
authors.lastname: Gasior
authors.forename: H J
authors.initials: HJ
authors.lastname: Linton
authors.forename: P
authors.initials: P
authors.lastname: Carpenter
authors.forename: H G
authors.initials: HG
authors.lastname: Rittenhouse
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D000918:Antibody Specificity; D001706:Biopsy; D006224:Cricetinae; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D017430:Prostate-Specific Antigen / Q000097:blood* / Q000276:immunology; D011471:Prostatic Neoplasms / Q000097:blood* / Q000276:immunology / Q000473:pathology; D020033:Protein Isoforms; D011498:Protein Precursors / Q000097:blood* / Q000276:immunology
chemical_list: C583834:(-2)pro-prostate-specific antigen, human; D000911:Antibodies, Monoclonal; D020033:Protein Isoforms; D011498:Protein Precursors; D017430:Prostate-Specific Antigen