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

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.

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

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,

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

Catalytic behaviour of acid phosphatase immobilized on natural supports in the presence of manganese or molybdenum

Synthetic complexes were formed by interaction between acid phosphatase and either tannic acid or natural allophanic clay, and used as model systems to simulate enzymatic reactions occurring in heterogeneous environment. The presence of Mn and Mo on the kinetic constants of the immobilized phosphatase was also tested. Complexes were prepared at 30 °C by interaction of acid phosphatase and tannic acid or allophanic clay in the presence and absence of Mn or Mo. The effect of the addition order of the metal (micronutrient in soils) to the clay–enzyme complexes was evaluated, as well. acid phosphatase immobilized on tannic acid and mineral clay showed variable activity levels. When phosphatase was immobilized on tannic acid, a recovery of about 51% of the initial enzymatic activity and a decrease of 17% of its catalytic efficiency was measured. The presence of Mn and Mo decreased the Vmax of phosphatase–tannic complexes as compared with that of the free phosphatase. All the added phosphatase molecules were immobilized onto the clay, when it was used as the immobilizing support. Phosphatase–clay complexes showed an increase of both enzymatic activity (higher Vmax value) and substrate affinity (lower Km values) as compared to the free enzyme, resulting in an increase by about 65% of the catalytic efficiency. The presence of Mn added at the same time with enzyme and clay decreased the enzymatic activity of the immobilized enzyme. However, when Mn was applied after the interaction of the enzyme with the clay, no significant effects on the residual activity of the immobilized enzyme were observed. Conversely, the order of the addition of Mo to the clay–enzyme complexes strongly influenced the activity and the kinetic behaviour of the immobilized enzyme. Moreover, Mo had higher inhibitory effects than Mn on phosphatase immobilized on both supports. The overall results seem to suggest that the immobilization of acid phosphatase on clay not only preserved but also enhanced the activity of the enzyme as compared with organic matter.

ARTICLE

Significance of Serum Tartrate-Resistant Acid Phosphatase in Rheumatoid Arthritis.

Abstract Human serum contains two related isoforms of tartrate-resistant acid phosphatase namely TRACP 5a and TRACP 5b. Serum TRACP 5a protein is increased in about 1/3 of RA sera. This study was undertaken to examine the significance of serum TRACP isoforms 5a and 5b as disease markers of inflammation and bone destruction in rheumatoid arthritis (RA). 118 patients were recruited including 50 with RA (25 with nodules), 26 with osteoarthritis (OA) and 42 with other rheumatic diseases. 26 healthy adults served as controls. Serum TRACP-5a activity, TRACP-5a protein and TRACP-5b activity were determined by in-house immunoassays. C-reactive protein (CRP) was determined by in-house immunoassay using commercial antibodies and CRP. Other commercial markers included bone-specific alkaline phosphatase (bALP), C-telopeptides of type-I collagen (ICTP), cartilage glycoprotein-39 (YKL-40), and IgM rheumatoid factors (IgM-RF). Mean TRACP-5a protein was significantly elevated only in RA compared to healthy control and other disease groups. TRACP 5a protein correlated significantly only with IgM-RF in RA. Among RA patients, mean TRACP 5a protein and IgM RF were significantly higher in nodule formers. In contrast, TRACP-5b activity was slightly elevated in RA and correlated with bALP. ICTP and YKL-40, but not with IgM-RF or CRP. Mean TRACP-5b activity was no different in RA patients with or without nodules. TRACP isoforms could be useful disease markers in RA: TRACP-5a protein may be a measure of systemic inflammatory macrophage burden and disease severity. TRACP-5b activity is a marker for osteoclast number and perhaps local or systemic bone destruction.