Specific Immunoassays for Detection of Intact and Cleaved Forms of the Urokinase Receptor

Piironen, Timo; Laursen, Birgitte Schantz; Pass, Jesper; List, Karin; Gårdsvoll, Henrik; Ploug, Michael; Danø, Keld; Høyer‐Hansen, Gunilla

doi:10.1373/clinchem.2004.038232

Cited by 60 publications

(70 citation statements)

References 35 publications

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“…Thus, biological variables should probably not be considered in isolation; more information can be derived from markers in combination. Markers that may be useful for analysis of PCa include the prostate-specific tissue kallikreins or other markers of local cancer progression, such as TGF-␤ 1 , interleukin-6 receptor (30 ), and the urokinase-like plasminogen activation cascade (31,32 ).…”

Section: Discussionmentioning

confidence: 99%

Comparison of Free and Total Forms of Serum Human Kallikrein 2 and Prostate-Specific Antigen for Prediction of Locally Advanced and Recurrent Prostate Cancer

et al. 2007

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Background:We evaluated the association of total and free forms of serum human kallikrein 2 (hK2) and prostate-specific antigen (PSA) with prostate cancers of unfavorable prognosis. Methods: We retrospectively measured total PSA (tPSA), free PSA (fPSA), and total hK2 (thK2) in preoperative serum samples from 867 men [and assessed free hK2 (fhK2) measured in 577 of these men] treated with radical prostatectomy for clinically localized prostate cancer. Associations between biomarker concentrations and extracapsular extension, seminal vesicle invasion, and biochemical recurrence (BCR) were evaluated. A subset of patients with PSA <10 g/L, the group most commonly seen in clinical practice in the US, was analyzed. Results: thK2 was the strongest predictor of extracapsular extension and seminal vesicle invasion (areas under the ROC curve [AUC], 0.662 and 0.719, respectively), followed by tPSA (AUC, 0.654 and 0.663). All biomarkers were significant predictors of BCR. hK2 forms, but not PSA forms, remained highly significant for predicting BCR in the low-PSA group. Combining tPSA, fPSA,

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Section: Discussionmentioning

confidence: 99%

Comparison of Free and Total Forms of Serum Human Kallikrein 2 and Prostate-Specific Antigen for Prediction of Locally Advanced and Recurrent Prostate Cancer

et al. 2007

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“…The assay design, performance characteristics and measurements of serum-levels using three uPAR immunoassays, TR-FIA 1, 2 and 3, designed for the highly sensitive and specific measurement of suPAR(I-III), suPAR(I-III) 1 suPAR(II-III) and suPAR(I) have been previously described in very extensive detail. 15,16 …”

Section: Volumetric Analysis Of the Prostate Glandmentioning

confidence: 99%

Free PSA isoforms and intact and cleaved forms of urokinase plasminogen activator receptor in serum improve selection of patients for prostate cancer biopsy

Steuber

Vickers

Haese

et al. 2007

Intl Journal of Cancer

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Clinicians currently use simple cut-points, such as serum prostatespecific antigen (PSA) 4 ng/ml, to decide whether to recommend further work-up for prostate cancer (PCa). As an alternative strategy, we evaluated multivariable models giving probabilities of a PCa diagnosis based on PSA and several circulating novel biomarkers. We measured total PSA, free PSA (fPSA), fPSA subfractions (single-chain fPSA-I and multichain fPSA-N), total human glandular kallikrein 2 (hK2) and full-length and cleaved forms of soluble urokinase plasminogen activator receptor (suPAR) in pretreatment serum from 355 men referred for prostate biopsy. Age and total PSA were combined in a ''base'' regression model to predict biopsy outcome. We then compared this base model to models supplemented by various combinations of circulating markers, using concordance index (AUC) to measure diagnostic discrimination. PCa prediction was significantly enhanced by models supplemented by measurements of suPAR fragments and fPSA isoforms. Addition of these markers improved bootstrap-corrected AUC from 0.611 for a cut-point and 0.706 for the base model to 0.754 for the full model (p 5 0.005). This improved diagnostic accuracy was also seen in subanalysis of patients with PSA 2-9.99 ng/ml and normal findings on DRE (0.652 vs. 0.715, p 5 0.039). In this setting, hK2 did not add diagnostic information. Measurements of individual forms of suPAR and PSA isoforms contributed significantly to discrimination of men with PCa from those with no evidence of malignancy. ' 2006 Wiley-Liss, Inc.

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“…Thus, the concentrations of the individual cleaved uPAR forms could be indicators of the activity of the plasminogen activation system, and the cleavage products may be stronger prognostic markers than the total amount of the uPAR forms. To test this hypothesis, we designed specific immunoassays to measure the individual uPAR forms (14 ). These assays demonstrated that the uPAR(I) concentration is a stronger prognostic factor than the total concentration of the uPAR forms (15 ).…”

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confidence: 99%

“…Our aim in the present study was to identify monoclonal antibodies (mAbs) with increased affinities for uPAR(I) to enable the design of a TR-FIA with an improved functional sensitivity. The uPAR mAb R3 has previously been characterized (8,14 ). mAb R20 is derived from a fusion between myeloma cells and spleen cells from female NIHS mice deficient in uPAR and immunized with human recombinant soluble uPAR from transfected Chinese hamster ovary cells.…”

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confidence: 99%

A New Assay for Measurement of the Liberated Domain I of the Urokinase Receptor in Plasma Improves the Prediction of Survival in Colorectal Cancer

et al. 2010

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BACKGROUND The liberated domain I of the urokinase plasminogen activator receptor [uPAR(I)] is a significant prognostic marker in lung and ovarian cancer, although the uPAR(I) concentration is below the limit of quantification (LOQ) in a substantial proportion of patient samples (Lung Cancer 2005;48:349–55; Clin Cancer Res 2008;14:5785–93; APMIS 2009;117:755–61). This study was undertaken to design an immunoassay with improved functional sensitivity for measuring uPAR(I) and to evaluate the prognostic value of uPAR(I) for colorectal cancer (CRC) patients. METHODS Surface plasmon resonance analysis identified 2 monoclonal antibodies, R3 and R20, that simultaneously bind to the liberated uPAR(I) but not to intact uPAR. We used R3 for capture and Eu-labeled R20 for detection in designing a 2-site sandwich time-resolved fluorescence immunoassay (TR-FIA 4) for measuring liberated uPAR(I). TR-FIA 4 was validated for use with citrated plasma. The prognostic value of the uPAR(I) concentration was evaluated in 298 CRC patients. The Cox proportional hazards model was used for the uni- and multivariate survival analyses. RESULTS The LOQ was 0.65 pmol/L. Liberated uPAR(I) was measurable in all patient samples with TR-FIA 4. In the multivariate analysis that included sex, age, tumor stage, tumor localization, and adjuvant treatment, the uPAR(I) concentration measured with TR-FIA 4 (hazard ratio, 1.72; 95% CI, 1.15–2.57; P = 0.009), as well as the concentration of intact soluble uPAR plus the cleaved uPAR fragment containing domains II and III, tumor stage, and age were independent predictors of prognosis. CONCLUSIONS TR-FIA 4 has a functional sensitivity improved 4-fold over that of the previous uPAR(I) assay. The uPAR(I) concentration measured with TR-FIA 4 is an independent predictor of prognosis in CRC patients.

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Specific Immunoassays for Detection of Intact and Cleaved Forms of the Urokinase Receptor

Cited by 60 publications

References 35 publications

Comparison of Free and Total Forms of Serum Human Kallikrein 2 and Prostate-Specific Antigen for Prediction of Locally Advanced and Recurrent Prostate Cancer

Comparison of Free and Total Forms of Serum Human Kallikrein 2 and Prostate-Specific Antigen for Prediction of Locally Advanced and Recurrent Prostate Cancer

Free PSA isoforms and intact and cleaved forms of urokinase plasminogen activator receptor in serum improve selection of patients for prostate cancer biopsy

A New Assay for Measurement of the Liberated Domain I of the Urokinase Receptor in Plasma Improves the Prediction of Survival in Colorectal Cancer

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