Abstract
Background: Serum tartrate-resistant acid phosphatase 5b (TRACP 5b) activity is a marker of osteoclast number and is elevated in breast cancer (BC) patients with extensive bone metastasis, which might in turn reflect the tumour burden.
We tested the hypothesis that baseline serum TRACP 5b activity and its interval change are potential prognostic markers of survival in BC patients with bone metastasis.
Methods: We analyzed the data from previous prospective studies. A total of 100 patients with newly diagnosed bone metastasis were included. Cox proportional regression model was used to evaluate the correlation between the overall
survival time (OS) and baseline serum TRACP 5b activity and its interval changes. The least significant change (LSC) of TRACP 5b was calculated from data obtained from 15 patients with early BC.
Results: Estrogen receptor status (Hazard Ratio (HR) = 0.397; p = 0.003) and visceral metastasis (HR = 0.492; p = 0.0045)were significantly correlated with OS. The OS was significantly shorter in those patients with higher baseline TRACP 5b
activity based on a cut-off value to delineate the highest tertile (HR = 3.524; p < 0.0001). Further analysis demonstrated that among patients in the highest tertile, OS was significantly longer in those patients who had achieved a decrease of
serum TRACP 5b activity greater than the LSC (38.59%) (p = 0.0015).
Conclusions: We found that TRACP 5b activity and its interval change after treatment bore a prognostic role in BC patients with bone metastasis and a high baseline serum TRACP 5b activity. Further prospective phase II study is necessary to confirm these results
Wednesday
Structural and functional analysis of human prostatic acid phosphatase
Prostatic acid phosphatase (PAP) is the most abundant phosphatase in human prostate tissue/secretions. PAP is a clinically important protein for its relevance as a biomarker of prostate carcinoma. Furthermore, it has a potential role in fertilization. We describe here most of the features of PAP including gene regulation, gene/protein structure, functions, its role in tumor progression and evolutionary features.
PAP has phosphatase activity and is an extensively studied biomarker of prostate cancer. The major action of PAP is to dephosphorylate macromolecules with the help of catalytic residues (His12 and Asp258) that are located in the cleft between two domains. This article will be of great interest to all those scientists who are working in the area of prostate pathophysiology
Authors: Hassan, Md Imtaiyaz1; Aijaz, Afnan; Ahmad, Faizan
Source: Expert Review of Anticancer Therapy, Volume 10, Number 7, July 2010 , pp. 1055-1068(14)
PAP has phosphatase activity and is an extensively studied biomarker of prostate cancer. The major action of PAP is to dephosphorylate macromolecules with the help of catalytic residues (His12 and Asp258) that are located in the cleft between two domains. This article will be of great interest to all those scientists who are working in the area of prostate pathophysiology
Authors: Hassan, Md Imtaiyaz1; Aijaz, Afnan; Ahmad, Faizan
Source: Expert Review of Anticancer Therapy, Volume 10, Number 7, July 2010 , pp. 1055-1068(14)
Thursday
Aminoquinoline Surfen Inhibits the Action of SEVI (Semen-derived Enhancer of Viral Infection)
Abstract
In semen, proteolytic peptide fragments from prostatic acid phosphatase can form amyloid fibrils termed SEVI (semen-derived enhancer of viral infection). These fibrils greatly enhance human immunodeficiency virus (HIV) infectivity by increasing the attachment of virions to target cells. Therefore, SEVI may have a significant impact on whether HIV is successfully transmitted during sexual contact.
Here, we demonstrate that surfen, a small molecule heparan sulfate proteoglycan antagonist, inhibits both SEVI- and semen-mediated enhancement of HIV type 1 infection. Surfen interferes with the binding of SEVI to both target cells and HIV type 1 virions but does not deaggregate SEVI fibrils. Because SEVI can increase HIV infectivity by several orders of magnitude, supplementing current HIV microbicide candidates with SEVI inhibitors, such as surfen, might greatly increase their potency.
Nadia R. Roan‡, Stefanie Sowinski‡, Jan Münch§, Frank Kirchhoff§ and Warner C. Greene‡¶,1
In semen, proteolytic peptide fragments from prostatic acid phosphatase can form amyloid fibrils termed SEVI (semen-derived enhancer of viral infection). These fibrils greatly enhance human immunodeficiency virus (HIV) infectivity by increasing the attachment of virions to target cells. Therefore, SEVI may have a significant impact on whether HIV is successfully transmitted during sexual contact.
Here, we demonstrate that surfen, a small molecule heparan sulfate proteoglycan antagonist, inhibits both SEVI- and semen-mediated enhancement of HIV type 1 infection. Surfen interferes with the binding of SEVI to both target cells and HIV type 1 virions but does not deaggregate SEVI fibrils. Because SEVI can increase HIV infectivity by several orders of magnitude, supplementing current HIV microbicide candidates with SEVI inhibitors, such as surfen, might greatly increase their potency.
Nadia R. Roan‡, Stefanie Sowinski‡, Jan Münch§, Frank Kirchhoff§ and Warner C. Greene‡¶,1
Tuesday
Safety and Immunological Efficacy of a DNA Vaccine Encoding Prostatic Acid Phosphatase in Patients With Stage D0 Prostate Cancer
Genitourinary Cancer
Purpose: Prostatic acid phosphatase (PAP) is a prostate tumor antigen. We have previously demonstrated that a DNA vaccine encoding PAP can elicit antigen-specific CD8+ T cells in rodents. We report here the results of a phase I/IIa trial conducted with a DNA vaccine encoding human PAP in patients with stage D0 prostate cancer.
Patients and Methods Twenty-two patients were treated in a dose-escalation trial with 100 µg, 500 µg, or 1,500 µg plasmid DNA, coadministered intradermally with 200 µg granulocyte-macrophage colony-stimulating factor as a vaccine adjuvant, six times at 14-day intervals. All patients were observed for 1 year after treatment.
Results: No significant adverse events were observed. Three (14%) of 22 patients developed PAP-specific IFN-secreting CD8+ T-cells immediately after the treatment course, as determined by enzyme-linked immunospot. Nine (41%) of 22 patients developed PAP-specific CD4+ and/or CD8+ T-cell proliferation. Antibody responses to PAP were not detected. Overall, the prostate-specific antigen (PSA) doubling time was observed to increase from a median 6.5 months pretreatment to 8.5 months on-treatment (P = .033), and 9.3 months in the 1-year post-treatment period (P = .054).
Conclusion: The demonstration that a DNA vaccine encoding PAP is safe, elicits an antigen-specific T-cell response, and may be associated with an increased PSA doubling time suggests that a multi-institutional phase II trial designed to evaluate clinical efficacy is warranted.
Supported by Grant No. K23 RR16489 from the National Institutes of Health (NIH; D.G.M., E.J.D.), by a production grant from the NIH National Gene Vector Laboratory Program, by the NIH National Center for Research Resources Clinical and Translational Science Award program (1UL1RR025011), and Grant No. W81XWH-05-1-0404 from the US Army Medical Research and Materiel Command Prostate Cancer Research Program (D.G.M., E.J.D., J.G.D., D.L.H., J.C.E.).
C. G. Drake
Immunotherapy for Prostate Cancer: Walk, Don't Run
J. Clin. Oncol., September 1, 2009; 27(25): 4035 - 4037.
Purpose: Prostatic acid phosphatase (PAP) is a prostate tumor antigen. We have previously demonstrated that a DNA vaccine encoding PAP can elicit antigen-specific CD8+ T cells in rodents. We report here the results of a phase I/IIa trial conducted with a DNA vaccine encoding human PAP in patients with stage D0 prostate cancer.
Patients and Methods Twenty-two patients were treated in a dose-escalation trial with 100 µg, 500 µg, or 1,500 µg plasmid DNA, coadministered intradermally with 200 µg granulocyte-macrophage colony-stimulating factor as a vaccine adjuvant, six times at 14-day intervals. All patients were observed for 1 year after treatment.
Results: No significant adverse events were observed. Three (14%) of 22 patients developed PAP-specific IFN-secreting CD8+ T-cells immediately after the treatment course, as determined by enzyme-linked immunospot. Nine (41%) of 22 patients developed PAP-specific CD4+ and/or CD8+ T-cell proliferation. Antibody responses to PAP were not detected. Overall, the prostate-specific antigen (PSA) doubling time was observed to increase from a median 6.5 months pretreatment to 8.5 months on-treatment (P = .033), and 9.3 months in the 1-year post-treatment period (P = .054).
Conclusion: The demonstration that a DNA vaccine encoding PAP is safe, elicits an antigen-specific T-cell response, and may be associated with an increased PSA doubling time suggests that a multi-institutional phase II trial designed to evaluate clinical efficacy is warranted.
Supported by Grant No. K23 RR16489 from the National Institutes of Health (NIH; D.G.M., E.J.D.), by a production grant from the NIH National Gene Vector Laboratory Program, by the NIH National Center for Research Resources Clinical and Translational Science Award program (1UL1RR025011), and Grant No. W81XWH-05-1-0404 from the US Army Medical Research and Materiel Command Prostate Cancer Research Program (D.G.M., E.J.D., J.G.D., D.L.H., J.C.E.).
C. G. Drake
Immunotherapy for Prostate Cancer: Walk, Don't Run
J. Clin. Oncol., September 1, 2009; 27(25): 4035 - 4037.
Thursday
Glycomic characterization of prostate-specific antigen and prostatic acid phosphatase in prostate cancer and benign disease seminal plasma fluids
Prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) are glycoproteins secreted by prostate epithelial cells, and have a long clinical history of use as serum biomarkers of prostate cancers.
These two proteins are present at significantly higher concentrations in seminal plasma, making this proximal fluid of the prostate a good source for purifying enough protein for characterization of prostate disease associated changes in glycan structures. With the use of seminal fluid samples representative of normal control, benign prostatic disease and prostate cancers, PAP and PSA were enriched by thiophilic absorption chromatography.
Released N-linked glycan constituents from both proteins were analyzed by a combination of normal phase HPLC and MALDI-TOF spectrometry. For PSA, 40 putative glycoforms were determined, and 21 glycoforms were determined for PAP. PAP glycans were further analyzed with a hybrid triple quadrupole/linear ion trap mass spectrometer to assign specific glycoform classes to each of the three N-linked sites. The glycans identified in these studies will allow for more defined targeting of prostate disease-specific changes for PAP, PSA and other secreted prostatic glycoproteins.
White KY, Rodemich L, Nyalwidhe JO, Comunale MA, Clements MA, Lance RS, Schellhammer PF, Mehta AS, Semmes OJ, Drake RR.
Department of Microbiology, Eastern Virginia Medical School, Norfolk, Virginia 23507, USA
These two proteins are present at significantly higher concentrations in seminal plasma, making this proximal fluid of the prostate a good source for purifying enough protein for characterization of prostate disease associated changes in glycan structures. With the use of seminal fluid samples representative of normal control, benign prostatic disease and prostate cancers, PAP and PSA were enriched by thiophilic absorption chromatography.
Released N-linked glycan constituents from both proteins were analyzed by a combination of normal phase HPLC and MALDI-TOF spectrometry. For PSA, 40 putative glycoforms were determined, and 21 glycoforms were determined for PAP. PAP glycans were further analyzed with a hybrid triple quadrupole/linear ion trap mass spectrometer to assign specific glycoform classes to each of the three N-linked sites. The glycans identified in these studies will allow for more defined targeting of prostate disease-specific changes for PAP, PSA and other secreted prostatic glycoproteins.
White KY, Rodemich L, Nyalwidhe JO, Comunale MA, Clements MA, Lance RS, Schellhammer PF, Mehta AS, Semmes OJ, Drake RR.
Department of Microbiology, Eastern Virginia Medical School, Norfolk, Virginia 23507, USA
Wednesday
Prostatic acid phosphatase, a neglected ectonucleotidase.
Two recent papers reveal that the soluble and secreted prostatic acid phosphatase, an enzyme that has long served as a diagnostic marker for prostate cancer, has a membrane-bound splice variant. This enzyme exhibits ecto-5'-nucleotidase activity, is widely distributed, and implicated in the formation of chronic pain.
While prostatic acid phosphatase hydrolyzes phosphomonoesters other than 5'-nucleoside monophosphates these novel data suggest that, in addition to ecto-5'-nucleotidase and the alkaline phosphatases, prostatic acid phosphatase must be taken into account in future studies on extracellular adenosine production.
Institute of Cell Biology and Neuroscience, Biocenter, Goethe-University, 60438, Frankfurt, Germany,
While prostatic acid phosphatase hydrolyzes phosphomonoesters other than 5'-nucleoside monophosphates these novel data suggest that, in addition to ecto-5'-nucleotidase and the alkaline phosphatases, prostatic acid phosphatase must be taken into account in future studies on extracellular adenosine production.
Institute of Cell Biology and Neuroscience, Biocenter, Goethe-University, 60438, Frankfurt, Germany,
Saturday
Prediction of bone metastases by combination of tartrate-resistant acid phosphatase, alkaline phosphatase and prostate specific antigen in patients wi
Choichiro Ozu, Jun Nakashima, Yutaka Horiguchi, Mototsugu Oya, Takashi Ohigashi and Masaru Murai, Keio University School of Medicine , Department of Urology, Tokyo, Japan
ABSTRACT
Objective: The clinical value of serum tartrate-resistant acid phosphatase (TRACP), prostate specific antigen (PSA), alkaline phosphatase (ALP), and prostatic acid phosphatase (PACP) for the prediction of bone metastases in prostate cancer were investigated.
Methods: TRACP, PACP, ALP, and psa serum levels were measured in 215 patients with prostate cancer, including 160 without and 55 with bone metastases. Correlation of serum marker levels with bone metastases was assessed using receiver operating characteristics (ROC) analysis. Sensitivity, specificity, accuracy, positive and negative predictive values were calculated for each serum marker. Multivariate stepwise logistic regression analysis was used to identify independent predictors for the presence of bone metastasis .
Results: Mean serum TRACP, PACP, ALP, and PSA levels were significantly elevated in patients with bone metastases compared with those without (P < 0.05). PSA and PACP levels increased significantly with clinical stage of the disease, whereas TRACP and ALP levels only increased significantly in stage D2. Serum TRACP levels correlated significantly with extent of disease on bone scans. ROC analyses showed no significant differences in area under the curve for these markers. Logistic regression analysis demonstrated that PSA, ALP, and TRACP were significant predictors of bone metastasis. Predicted and observed risks of bone metastasis were well correlated when TRACP, ALP, and PSA were combined and bone scan could have been omitted in 70% of patients by assessing these three markers.
Conclusions: Serum TRACP can be considered a useful predictor of bone metastases in prostate cancer. A combination of TRACP, ALP, and PSA can obviate the need for a bone scan in 70% of cases.
International Journal of Urology
Volume 15 Issue 5, Pages 419 - 422
Published Online: 28 Mar 2008
ABSTRACT
Objective: The clinical value of serum tartrate-resistant acid phosphatase (TRACP), prostate specific antigen (PSA), alkaline phosphatase (ALP), and prostatic acid phosphatase (PACP) for the prediction of bone metastases in prostate cancer were investigated.
Methods: TRACP, PACP, ALP, and psa serum levels were measured in 215 patients with prostate cancer, including 160 without and 55 with bone metastases. Correlation of serum marker levels with bone metastases was assessed using receiver operating characteristics (ROC) analysis. Sensitivity, specificity, accuracy, positive and negative predictive values were calculated for each serum marker. Multivariate stepwise logistic regression analysis was used to identify independent predictors for the presence of bone metastasis .
Results: Mean serum TRACP, PACP, ALP, and PSA levels were significantly elevated in patients with bone metastases compared with those without (P < 0.05). PSA and PACP levels increased significantly with clinical stage of the disease, whereas TRACP and ALP levels only increased significantly in stage D2. Serum TRACP levels correlated significantly with extent of disease on bone scans. ROC analyses showed no significant differences in area under the curve for these markers. Logistic regression analysis demonstrated that PSA, ALP, and TRACP were significant predictors of bone metastasis. Predicted and observed risks of bone metastasis were well correlated when TRACP, ALP, and PSA were combined and bone scan could have been omitted in 70% of patients by assessing these three markers.
Conclusions: Serum TRACP can be considered a useful predictor of bone metastases in prostate cancer. A combination of TRACP, ALP, and PSA can obviate the need for a bone scan in 70% of cases.
International Journal of Urology
Volume 15 Issue 5, Pages 419 - 422
Published Online: 28 Mar 2008
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