MULTIPLE FORMS OF PROSTATE-SPECIFIC ANTIGEN AND THE INFLUENCES OF IMMUNOASSAY DESIGN ON THEIR MEASUREMENT IN PATIENT SERUM

Over the past several years, published studies have presented evidence confirming that multiple forms of prostate-specific antigen (PSA) are present in human serum, This heterogeneity is of two distinct types, One form is that of the various complexes PSA (a serine protease) take s with the endogenous protease inhibitors naturally present in serum, These include alpha(1)-antichymotrypsin (alpha(1)-ACT) and the multime ric alpha(2)-macroglobulin (alpha(2)-M), Additionally, uncomplexed fre e PSA is separable into a number of charge-related isomers, The observ ation that a portion of PSA may be isolated from sera as a free form a nd that the molar ratio of serum inhibitors is in large stoichiometric excess suggests that enzymatically inactive PSA is of clinical signif icance, Using two commercially available assay formats, we present com parative studies of patient sera fractionated to isolate complexed and free forms of PSA, Results show that significant amounts of PSA are p resent as a complex with alpha(2)-M and are not quantifiable by any of the current immunoassays, Studies describing issues of assay design i ncluding the use of monoclonal versus polyclonal antibodies, the natur e of the solid phase matrix, assay kinetics, and differences in the re activity of artificial assay standards compared with the endogenous fo rms of PSA present in the patient sample are also presented, These var iables are responsible for some of the differences seen among assays, In addition, the overriding issue in assay comparability is that there is currently a lack of consensus on uniform procedures for the standa rdization of PSA assays.