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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate-specific antigen (PSA) in serum is primarily complexed with alpha 1-antichymotrypsin (alpha 1-ACT). However, 12-15% of prostate cancer (PCa) patients present with the predominant form being uncomplexed (free) PSA (Lilja et al., Clin Chem 1991;37:1618-24). We report that commercial immunoassays demonstrate variations in reactivity, especially to the uncomplexed form. We fractionated and analyzed commercial controls, PSA complexes prepared in vitro, and sera from patients with PCa or benign prostatic hyperplasia, using molecular sieve chromatography and Hybritech Tandem-R, Abbott IMx, and Ciba Corning ACS PSA assays. Peak integration of PCa samples demonstrated ACS:Tandem-R ratios of 1-1.3 for PSA/alpha 1-ACT complex. In contrast, ratios of uncomplexed peaks ranged from 2 to 4, suggesting a greater reactivity of the uncomplexed form in the ACS PSA assay. Discrepancies between assays, when PSA was measured in unfractionated sera, correlated directly with the percentage of the uncomplexed form. In controls, fractionation revealed the presence of uncomplexed PSA only, with ratios of ACS:Tandem-R and IMx:Tandem-R of 3:1 and 1.8:1, respectively. Immunoblots of PCa sera detected uncomplexed PSA (approximately 30 kDa) and PSA complexes of approximately 95 kDa (PSA/alpha 1-ACT) and > 200 kDa, indicative of alpha 2-macroglobulin. Maximal recognition of all forms of PSA may be important for early detection of disease progression.
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PMID:Multiple forms of prostate-specific antigen in serum: differences in immunorecognition by monoclonal and polyclonal assays. 752 44

The physician and laboratorian have several proven PSA assays from which to choose, and several more are likely to achieve FDA approval soon. Furthermore, an assay that is FDA approved offers considerable reassurance that the many aspects of assay design and manufacturing processes meet an acceptable standard. This will become even more critical as assays report values in the ultrasensitive range. We have attempted to review here some of the most important issues related to PSA assay performance and standardization. Standardization particularly is a complex problem for which solutions are just now appearing. Yet efforts must continue to minimize controversies, because many more assays will be forthcoming and because newer applications of PSA determinations will place more pressure on proper assay evaluations. For example, measurement of free PSA, PSA-ACT complexes, and the ratio of one to the other are intriguing possibilities for added clinical benefit. Also, ultrasensitive PSA assays add a new dimension to the detection of residual disease and may provide unique opportunities for the implementation of new therapies and their timely evaluation. In our opinion, the impact of PSA on the management of prostate cancer is still growing, and the opportunities for better and new assays are still great.
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PMID:Issues in the assessment of PSA immunoassays. 750 68

Prostate specific antigen is an abundant prostate-derived serine protease in the seminal fluid. Low concentrations of the protein are normally released into blood, but above normal concentrations are frequently detected in prostate disease. The PSA-ACT complex is the predominant molecular form of serum PSA (up to approximately 95%) although complex formation is slow between the purified proteins in vitro. A free, noncomplexed form of PSA constitutes a minor fraction of the serum PSA, although serum ACT occurs in large molar excess. The free, noncomplexed form of serum PSA is reported to constitute a significantly smaller proportion of the PSA in untreated prostate cancer than in BPH. The molecular basis for this finding is unclear, but measurements of the proportion of the free form of serum PSA or the proportion of serum PSA-ACT may facilitate discrimination between prostate cancer and BPH.
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PMID:Significance of different molecular forms of serum PSA. The free, noncomplexed form of PSA versus that complexed to alpha 1-antichymotrypsin. 750 76

The absolute tissue specificity of prostate specific antigen (PSA) allows the use of PSA test not only for detecting recurrence or metastasis at an early stage after radical prostatectomy but also for screening prostate cancer if combined with digital rectal examination. There is also a need to improve the current PSA test to better differentiate between prostate cancer and benign prostate hyperplasia (BPH). Because of these clinical applications, a much greater demand was placed on PSA test for extra sensitivity, accuracy, and precision even within the normal PSA concentration range. However, the current commercial assay kits for PSA do not provide correct PSA values. Many factors contributing to the problem include the specificity of the anti-PSA antibodies, the composition of the calibrator, the PSA values assigned to the calibrator, the PSA isoform used for anti-PSA antibody preparation, the test design, and the composition of the diluent. Most problems were derived from the failure of realizing earlier that the majority of the PSA exists in serum not as free PSA but as complexes with protease inhibitors. Other problems, such as constantly changing composition of various forms of PSA in serum specimens, and different clearance rates for various forms of PSA make almost impossible to develop an ideal assay for PSA. Therefore, we suggest that test should be designed for measuring PSA-ACT (PSA-alpha 1-antichymotrypsin) complex only. Changing the focus from the measurement of total PSA of various forms to the PSA-ACT complex alone may improve the differentiation between prostate cancer and BPH but may also simplify the selection of anti-PSA antibodies and the preparation of calibrator for the assay.
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PMID:Assay for prostate specific antigen (PSA): problems and possible solutions. 751 21

Prostate cancer can be detected at an early, potentially curable stage by screening based on digital rectal examination and serum prostate specific antigen (PSA). The value of screening appears doubtful, based on high 10-year survival rates in selected cases of early prostate cancer, but this follow-up time may be insufficient. By linking the information on 21172 men who took part in a screening examination in Finland, 1968-73, with data from the Finnish Cancer Registry, 44 cases of prostate cancer diagnosed up to 1980 were identified. Serum samples from cancer cases and from 74 controls matched for age and time of sampling were assayed for PSA and its complex with alpha 1-antichymotrypsin (PSA-ACT). With a cut-off for PSA of 2.5 micrograms/L giving 92% specificity, 95% of the cancers developing within the first 5 years, and 52% developing in 6-10 years tested positive. As a potential screening test with a 5-year interval for men under 65, the sensitivity would be 92% and specificity 97%. The ratio of PSA-ACT to total PSA was lower in controls than in patients with cancer. Using this ratio, we could eliminate half of the false-positive results in the range 2.5-25 micrograms/L without loss of sensitivity. Cancer was typically diagnosed 5-10 years after PSA exceeded 2.5 micrograms/L, and the median survival after diagnosis was 3.6 years. 10-year survival after drawing the sample was 71% in cancer cases with a PSA concentration less than 4 micrograms/L and 48% in those with higher concentrations. The corresponding figures at 15 years were 53% and 27%, and at 20 years 43% and 18%, respectively. These results suggest it is advisable to confine screening for prostate cancer to men with a life expectancy of clearly more than 10 years--ie, younger men, who have the greatest chance to benefit from early detection.
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PMID:Serum concentrations of prostate specific antigen and its complex with alpha 1-antichymotrypsin before diagnosis of prostate cancer. 1133 Feb 69

The current assays for serum prostate specific antigen (PSA) have failed to produce the same PSA values on the same specimens because of problems with antibody specificity and calibrator preparation. To eliminate these problems, we proposed to replace the current serum PSA assay with an assay specific for the PSA-ACT (PSA-alpha 1-antichymotrypsin) complex in the serum. An assay specific for the PSA-ACT complex was established using the anti-PSA antibody to coat the microplate for capturing the PSA complex and anti-ACT polyclonal antibodies for quantification. There was an excellent correlation between serum concentrations of PSA-ACT and total PSA, using either the Hybritech calibrator (gamma = 0.996) or a serum calibrator prepared in house (gamma = 0.993), in random as well as in serial specimens from 14 individual patients. Even though we did not find a gradual increase in the percentage of PSA-ACT with the increase of total PSA in cancer patients, a slightly higher percentage of free PSA was measured in pooled normal sera (18%) and in pooled sera containing only 12 ng/ml of total PSA (12%), compared to serum pools containing elevated PSA (> 100 ng/ml) level, in which most PSA was in the complex form (95%). Therefore, using an assay that specifically measures the PSA-ACT complex in the serum not only simplifies the preparation of calibrator but eliminates the difficulty of antibody selection, it also allows various assay kits to produce identical PSA values and also improve the test specificity for prostate cancer.
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PMID:Correlation of serum concentrations of PSA-ACT complex with total PSA in random and serial specimens from patients with BPH and prostate cancer. 753 35

Standardization of determinations for prostate specific antigen (PSA) has become an important issue due to the widespread use of these determinations for prostate cancer screening. Standardization of this assay is complicated due to the occurrence of two major forms of PSA in serum, the free antigen and a complex between PSA and alpha 1-antichymotrypsin (PSA-ACT). These two forms of PSA are recognized differently by different antibodies, but by careful selection of antibodies, it is possible to design methods that measure each form equally. It is suggested, that standards for PSA and PSA-ACT should be prepared and established as international standards. Furthermore, reference methods should be established on the basis that these standards and carefully selected reference antibodies.
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PMID:Standardization of PSA determinations. 754 84

We made an effort to identify a reliable source for obtaining large quantities of both free (PSA) and PSA-ACT complex for the preparation of the calibrator for the PSA assay. Using size exclusion chromatography, we found both free PSA and PSA-ACT complex in the conditioned cell medium of the LNCaP cell line, which was derived from a human metastatic adenocarcinoma of the prostate. An assay specific for PSA-ACT reacted only with the PSA-ACT complex from cells grown in serum-free medium, and not with the complex from the cell medium grown in 10% calf serum. We also found both free PSA and PSA-ACT complex in 15% of cytosols prepared from breast tumor tissues; the cytosol PSA concentrations ranged from 0.1 to 110 ng/ml. No correlation was found between cytosol PSA and concentrations of estrogen receptor, progestin receptor, epidermal growth factor receptor, cathepsin D, or the ectodomain of c-erbB-2 protein. Based on chromatographic characterizations and the slope of their dose-response curves, it appears that both free PSA and PSA-ACT complex found in the cytosols are similar to PSA complex from the cell medium and the serum of prostate cancer patients. Ectopic PSA was also detected in pooled sera from patients with breast, ovarian, pancreatic, and colon carcinoma. The PSA concentrations in these serum pools increased with the level of their dominant tumor marker. In any event, the LNCaP cell medium appears to be a reliable source for obtaining both free and ACT-complexed PSA of human tumor origin for the preparation of PSA assay calibrators.
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PMID:PSA immunoreactivity detected in LNCaP cell medium, breast tumor cytosol, and female serum. 756 42

Prostatic tissue specimens derived from transurethral resections of patients with metastatic prostate cancer were analyzed for genetic alterations in the hormone-binding domain of the androgen receptor (AR) gene. Direct sequencing of the polymerase chain reaction-derived DNAs of 6 of 24 specimens revealed a codon 877 mutation (ACT-->GCT, Thr-->Ala) in the hormone-binding domain of the AR gene. This same AR mutation has been reported previously in a metastatic prostate cancer cell line, LNCaP, where this mutation confers upon the AR an altered ligand-binding specificity which is stimulated by estrogens, progestagens, and antiandrogens. It is possible that analogous to an activated/altered growth factor receptor oncogene, codon 877 mutant AR with altered ligand binding may provide a selective growth advantage in the genesis of a subset of advanced prostate cancer. Although estrogens are used infrequently, antiandrogens are used increasingly in hormonal therapy for patients with advanced prostate cancer. The stimulatory effect of these therapeutic agents on the codon 877 mutant AR further suggests that this frequently observed AR mutation may contribute to the treatment refractory disease.
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PMID:Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers. 818 68

Prostate-specific antigen (PSA) is the most important tumor marker for early detection and monitoring of prostate cancer (PCa) patients. PSA is also elevated in many patients with benign prostatic hyperplasia (BPH). The study of the serum PSA forms, free PSA (f-PSA) and PSA complexed with alpha 1-antichymotrypsin (PSA-ACT), may improve the discrimination between PCa and BPH. An immunoassay specific for f-PSA is reported with very low cross-reactivity (0.7%) to PSA-ACT. Serum specimens from BPH and PCa patients (determined by biopsy) with PSA levels from < 1 to > 100 ng/ml were tested. No f-PSA was detected in serum specimens from normal females (N = 50). Low levels (0-0.3 ng/ml) were detected in specimens from healthy males (N = 60). In specimens from PCa and BPH patients, the f-PSA to total PSA ratio (f/t) was found to range from 1% to higher than 60%. While maintaining an 80% sensitivity for cancer, the f/t ratio improved specificity to approximately 80%, as compared to 55% for total PSA alone. The receiver operating characteristics (ROC) curve analysis of the f/t ratio displayed a greater area under the plot (0.84) compared to total PSA alone (0.745). The results demonstrate that the f/t ratio significantly increases specificity for PCa detection compared to total PSA alone, showing the potential clinical value of the f-PSA immunoassay.
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PMID:Dual monoclonal antibody immunoassay for free prostate-specific antigen. 854 76


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