Highlights on the Canine Prostatic Specific Esterase (CPSE): A diagnostic and screening tool in veterinary andrology.

In the last years, the need to look for an accurate and precise diagnosis of prostatic diseases in dogs has grown. Among other diagnostic tools, the seric CPSE has been studied and identified as a valid and specific biomarker for prostatic disorders, since it can result significantly more elevated in dogs affected by several prostatic abnormalities, such as benign prostatic hyperplasia, bacterial prostatitis and prostatic carcinoma. Therefore, dosing CPSE in serum represents a new diagnostic and screening tool. Dosing CPSE in everyday clinical practice has three objectives: (a) the diagnosis of benign prostatic hyperplasia; (b) the preventive screening of prostatic disorders in healthy dogs; (c) the medical follow-up in subjects with prostatic disorders during and after medical therapy. Neither circadian rhythms nor transrectal palpation performed during the andrological examination do affect CPSE. A sexual rest of at least 24 hr before dosing CPSE is recommended as it is affected by ejaculation.

Expression of cyclo-oxygenases-1 and -2, and microsomal prostaglandin E synthase-1 in penile and preputial papillomas and squamous cell carcinomas in the horse.

REASONS FOR PERFORMING STUDY: Penile and preputial papilloma and squamous cell carcinoma (SCC) are commonly diagnosed in horses. Papillomas have the potential to progress to potentially lethal SCC. Knowledge of pathogenetic mechanisms may help in prevention and definition of treatment targets. STUDY DESIGN: Retrospective study using archived material. OBJECTIVES: To determine the expression of cyclo-oxygenase 1 (COX-1), cyclo-oxygenase 2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) in penile and preputial normal tissue, papilloma and SCC in horses, and whether expression of these enzymes is influenced by degree of inflammation and differentiation grade. METHODS: Tumour differentiation grade, degree of inflammation and COX-1, COX-2 and mPGES-1 expression in 75 formalin-fixed paraffin embedded samples of penile and preputial papilloma and SCC of 68 horses were investigated by histopathology and immunohistochemistry. RESULTS: Inflammation was more prominent in SCC compared with papilloma. No correlation between expression of COX-1 or COX-2 and inflammation was found. Expression of mPGES-1 was weakly correlated with inflammation. Expression of COX-1, COX-2 and mPGES-1 was found in 42.6%, 50.7% and 96.0% of lesions respectively, but less than 1% of cells were immunopositive for COX-1 and COX-2 in 59.4% and 84.2% of cases respectively. Expression of COX-1 was moderately negatively correlated with differentiation grade, COX-2 was not correlated and mPGES-1 was poorly negatively correlated. CONCLUSIONS: Expression of COX-1 and COX-2 in penile and preputial SCC in the horse is poor and COX inhibitors may thus be of little value for prevention or treatment. Microsomal PGES-1 is more prominently expressed in well-differentiated tissue compared with poorly differentiated tissue. Further research on the role of mPGES-1 in carcinogenesis is needed to assess its potential use as a treatment target. Knowledge of arachidonic pathway enzyme expression and their role in equine penile and preputial carcinogenesis may help in developing preventive and therapeutic strategies.

Elevated LDH predicts poor outcome of recurrent germ cell tumours treated with dose dense chemotherapy.

AIMS OF THE STUDY: Prognostic factors for recurrent germ cell tumours (GCTs) treated with dose dense salvage chemotherapy have not been identified. This study determines whether lactate dehydrogenase (LDH) or established prognostic models can predict the outcome of recurrent GCTs treated with dose dense cisplatin-based chemotherapy. PATIENTS AND METHODS: Retrospective analysis of 117 consecutive male patients with a first recurrence of a GCT treated with dose dense chemotherapy at a single cancer centre. Characteristics associated with progression-free survival (PFS) and overall survival (OS) were identified by univariate and multivariate analyses. Prognostic criteria published by the Medical Research Council (MRC) and the Memorial Sloan Kettering Cancer Centre (MSK) were also applied in an attempt to validate them and to compare their performance to that of LDH. RESULTS: Raised LDH was significantly associated with poor PFS (hazard ratio (HR)=3.7; p<0.001) and OS (HR=3.4; p=0.001). Further factors associated with poor PFS and OS, respectively, were failure to achieve a complete response or marker negative partial response for at least 6 months (HR=2.1; p=0.033) and seminoma histology (HR=3.4; p=0.003). The MRC prognostic model, but not the MSK model, identified groups of patients with statistically significant differences in PFS and OS but raised LDH predicted OS and PFS with a higher HR. CONCLUSIONS: Raised LDH is associated with a poor prognosis in recurrent GCTs and outperforms established prognostic models in this setting. LDH as a prognostic factor should be validated prospectively and should also be assessed in patients receiving conventional dose chemotherapy regimens.

[Cyclooxygenase 2 inhibitors and urologic and gynaecologic cancers]. / Inhibiteurs de la cyclo-oxygénase 2 et cancers urogénitaux.

PGE2 is one of the most important prostaglandin involved in the oncogenesis. PGE2 is found at high concentration level in the most of epithelial cancer. Urologic and gynaecologic cancer express the enzyme which are at the origin of PGE2: cyclooxygenase 2. Cox2 inhibitors present anticancer properties demonstrated in wide varieties of cellular and animal models. Human applications are currently tested in many clinical trials for bladder, prostate and uterine carcinomas.

Essential stations in the intracellular pathway of cytotoxic bovine seminal ribonuclease.

Bovine seminal RNase (BS-RNase) is a dimeric RNase selectively cytotoxic for malignant cells. No information is available on its pathway from the extracellular matrix through the cytosol, where it degrades rRNA. An investigation of this pathway is reported here, carried out by immunofluorescence studies, by assessing the effects on BS-RNase cytotoxicity of drugs that affect specific intracellular compartments and by assaying the behaviour of a protein variant, BS-RNase-KDEL (BS-RNase in which a Lys-Asp-Glu-Leu peptide segment is inserted at the C-terminal ends of the subunit chains), endowed with a consensus sequence that directs proteins to the endoplasmic reticulum. BS-RNase was found to bind both normal and malignant cells and to be internalized by both cell types in endosome vesicles. Non-cytotoxic RNases, such as RNase A and a monomeric derivative of BS-RNase, did not bind to the cell surface and were not internalized. However, an engineered, dimeric and cytotoxic variant of RNase A bound effectively and permeated cells. The results of immunofluorescence studies, the effects of nigericin, monensin and brefeldin A on the cytotoxic action of seminal RNase, and the behaviour of the BS-RNase-KDEL variant, led to the conclusion that the pathway of BS-RNase in malignant cells from the extracellular matrix to the cytosol has two essential intracellular stations: endosomes and the trans-Golgi network. In normal cells, however, the protein does not progress from the endosomal compartment to the Golgi complex.

Telomerase in urological malignancy.

PURPOSE: Telomerase is a ribonucleoprotein enzyme that compensates for the progressive erosion of chromosomal ends, called telomeres. In most somatic cells telomerase expression is repressed and telomeres progressively shorten after each cell division, causing cell senescence. Conversely telomerase is active in most human cancers, maintaining the integrity of chromosome ends and representing an important step in cell immortalization and carcinogenesis. The large and increasing interest in telomerase was motivated by the demonstration that more than 90% of human cancers are telomerase positive, whereas most normal tissues or benign tumors contained low or undetectable telomerase activity. We addressed the most recent data on telomerase detection in urological malignancy. Approaches to telomerase inhibition as a future anti-cancer therapy are also discussed. MATERIALS AND METHODS: We comprehensively reviewed the most recent and significant publications in this field using current issues of specific journals and a MEDLINE search. RESULTS: Telomerase is often expressed in bladder (90%), prostate (80%) and renal (69%) carcinoma. A variable but significant percent of normal tissues from tumor adjacent zones or noncancer samples are positive for telomerase. The clinical role of telomerase is still questionable in renal cancer, while important insights into the diagnostic role of telomerase in bladder and prostate carcinoma are increasing. Telomerase detection in exfoliated cells collected with urine or bladder washings seems a promising tool for the diagnosis and management of bladder cancer. CONCLUSIONS: Larger perspective studies of larger groups of patients are required to discover an appropriate role for telomerase when assessing these tumors. The improvement of quantitative methods to evaluate the expression of telomerase is a cornerstone in the complete clarification of the clinical relevance of telomerase.

Glutathione S-transferase in hormonal carcinogenesis.

Treatment with testosterone propionate (TP) and diethylstilbestrol (DES) or TP and estradiol (E2) for 8-9 months causes development of leiomyosarcomas in the vas deferens or uterus of Golden Syrian hamsters at a frequency of 100%. In males, treatment with estrogens alone results in renal tumors, fatal within 6 months. No leiomyosarcomas have been detected after treatment with estrogens alone, perhaps due to this high mortality rate. In tissue culture, treatment with the glucocorticoid (GC) triamcinolone acetonide (TA) results in an increased expression of a mu-class glutathione S-transferase (GST) (hGSTYBX). We have characterized this induction as a secondary response, i.e. requiring new protein synthesis. Here we describe homologies to known transcription factor-binding sites in the hGSTYBX promoter which may be involved in the induction event. hGSTYBX is a member of a superfamily of detoxification enzymes, induced by genotoxic compounds and reactive oxygen species (ROS). We also describe the effects of several known inducers of other GST family members on hGSTYBX. While implicated in many chemotherapeutic-resistant tumors, GST enzymes have not yet been characterized as a functional agent in hormonal carcinogenesis. This latter possibility is the focus of our investigations. To study the effects of hormone treatment on GST levels in vivo, we have developed a polyclonal antibody to hGSTYBX, and conducted immunohistochemistry on tissues from control and treated animals. Treatment with TP and E2 causes a loss of hGSTYBX expression in the epithelium of the vas deferens. We hypothesize that the loss of this protective enzyme leaves the cells vulnerable to the genotoxic effects of estrogen or estrogenic metabolites.

Group II phospholipase A2 in human male reproductive organs and genital tumors.

BACKGROUND: Group II phospholipase A2 (PLA2) is a lipolytic enzyme suggested to play a role in inflammation and antibacterial defence. In seminal fluid, the concentration of PLA2 is exceedingly high under normal circumstances (about 1,000 times the concentration in blood plasma of healthy humans). To elucidate the origin of the enzyme present in seminal plasma, we investigated the expression of group II PLA2 in male reproductive organs both at protein and mRNA levels. In addition, the presence of the enzyme was studied in common male genital tumors. METHODS: The methods used were immunocytochemistry, in situ hybridization, and Northern blotting. RESULTS: Northern blotting gave positive results for group II PLA2 mRNA in normal prostate, whereas other normal genital tissues gave negative results. Immunohistochemistry and in situ hybridization of group II PLA2 gave identical results. The enzyme was produced exclusively by the secretory epithelial cells of the prostatic gland. Surprisingly, expression was restricted to the posterior lobe and paraurethral glands of the prostate. Cells of prostatic adenocarcinoma expressed group II PLA2, whereas cells of other male genital tumors contained neither the enzyme protein nor the mRNA of group II PLA2. In some cases prostatic cancer cell seemed to express group II PLA2 at a higher rate than normal prostatic gland cells. CONCLUSIONS: The high content of group II PLA2 in seminal plasma is due to the local production and secretion of the enzyme by the epithelial cells of the prostatic glands. Group II PLA2 is expressed focally, suggesting that specialized prostatic glands secrete this enzyme. All prostatic adenocarcinomas tested expressed group II PLA2 in variable amounts.

Interferon for the therapy of condyloma acuminatum.

Lymphoblastoid interferon, Wellferon, was used to treat patients with resistant and persistent condyloma acuminatum at initial doses of 5, 3, and 1 million unit/square meter (Mu/M2). The objectives of this study were to evaluate the efficacy and toxicity of, and tolerance to, intramuscular and intralesional interferon. Seventeen patients were treated with 5 Mu/M2, 14 patients with 1 Mu/M2, and 37 patients with 3 Mu/M2; daily administration was followed by three-times-a-week dosing. The complete response rate in patients receiving initial dose of interferon of 5 Mu/M2 was 69%, that for doses of 1 Mu/M2 was 43%, and that for doses of 3 Mu/M2 was 57%. All patients given interferon developed initial elevations of temperature of limited duration, whereas all patients given the 5 Mu/M2 dose had to have the amount reduced because of biologic side effects. However, only five of 37 (14%) of the patients given 3 Mu/M2 required a reduction in the dosage, and no patient given 1 Mu/M2 needed to have the dosage reduced. These studies suggest that interferon is efficacious in the treatment of resistant and persistent condyloma acuminatum, and that the biologic side effects were dose-related, well tolerated, and not life-threatening.