Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent clinicopathologic studies have shown that many prostatic adenocarcinomas express focal neuroendocrine differentiation and that neuroendocrine differentiation is most apparent in advanced anaplastic tumors. While studying growth-regulatory signal transduction events in human prostate carcinoma cell lines, we found that in two of four cell lines, the androgen-sensitive line LNCaP and the highly metastatic androgen-independent line PC-3-M, elevation of cAMP through addition of cAMP analogues or phosphodiesterase inhibitors induced a markedly neuronal morphology. Also in LNCaP cells ultrastructural analysis showed that cAMP induced the appearance of neurosecretory cell-like dense-core granules. Phenotypic analysis of untreated LNCaP and PC-3-M cells showed that both cell lines express markers of the neural crest including S-100, chromogranin A, pp60c-src, and neuron-specific enolase as well as the epithelial marker KS1/4 and stage-specific embryonic antigen 4. In PC-3-M cells, cAMP markedly elevated neuron-specific enolase protein and caused an increase in the specific activity of the neuroendocrine marker pp60c-src, and in both cell lines expression of KS1/4 and stage-specific embryonic antigen 4 was down-regulated. In addition to effects on lineage markers, cAMP treatment induced G1 synchronization, growth arrest, and loss of clonogenicity, indicating terminal differentiation. Our data provide direct evidence of plasticity in the lineage commitment of adenocarcinoma of the prostate. We have shown that cell-permeant cAMP analogues can induce terminal differentiation, suggesting that hydrolysis-resistant cyclic nucleotides may present an additional approach to the treatment of advanced prostate cancer.
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PMID:Terminal neuroendocrine differentiation of human prostate carcinoma cells in response to increased intracellular cyclic AMP. 820 89

To correlate molecular changes with clinical information in prostate tissue, it is necessary to have accurate methods for screening for mutations in clinically available specimens. We have refined the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis for detection of p53 mutations in routine pathology specimens. These improvements help overcome technical barriers that interfere with SSCP analysis of archival tissues when only small amounts of poorly preserved formalin-fixed DNA are available. Furthermore, prostate samples are heterogeneous in containing tumor, normal tissue, and hyperplastic tissue. To address the first issue, the method included an initial selection of PCR products using exonuclease I, followed by a second-step selection using nested PCR. This step ensures adequate amplification of the target sequence while minimizing artifactual products that could otherwise interfere with mutation analysis. For the second issue, in addition to morphologic selection of appropriate tissue areas, we improved the sensitivity of detection of mutations by using restriction enzyme digestion of products prior to SSCP analysis. Detection of mutations in heterogeneous tissue was evaluated by determining the minimal detectable mutant allele frequencies in exons 4, 5, 6, 7, 8-9, and 10 by using mixtures of known mutant and wild-type cell lines, which were found to be 17.6, 9.1, 12.5, 8.1 14.0, and 14.3%, respectively. To determine the utility of this method when used on heterogeneous clinical samples, we performed study of 19 archival prostate specimens (14 primary prostate cancers, three benign prostatic hyperplasia and two metastases) and detected abnormally migrating products in six of the prostate cancer specimens (four primaries and two metastases). In five of these samples, there was sufficient DNA to perform sequencing, which disclosed single-base change mutations in all five samples.
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PMID:Identification of p53 mutations in archival prostate tumors. Sensitivity of an optimized single-strand conformational polymorphism (SSCP) assay. 895 19

Urology is a specialty with many branches, including urological oncology with 25% of all cancers. Development in certain areas been very rapid, for instance with the introduction of minimally and non-invasive methods such as ESWL and phosphodiesterase inhibitors, innovations which have brought obvious improvements and have been promptly adopted in clinical practice. In other areas such as chronic abacterial prostatitis and renal cancer, progress has been very limited. Still other areas have seen useful but less spectacular improvements for which it has taken time, clinical experience and a multitude of clinical studies before they have been embraced in daily clinical practice. Examples of these more gradual developments are hyperthermia for the treatment of benign prostatic hyperplasia and transrectal ultrasound in prostate cancer.
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PMID:[Both major breakthroughs and stagnation in urology. Industry, together with clinicians, are responsible for most innovations]. 1143 74

The LNCaP cell line is a versatile and useful model suitable for the study of human prostate cancer in vitro. It has been determined that the elevation of LNCaP intracellular cyclic adenosine monophosphate (cAMP) levels through the addition of membrane-permeable cAMP analogs, phosphodiesterase inhibitors, adenylate cyclase activators, or components of the cAMP signal-transduction pathway can induce reversible neuroendocrine (NE) differentiation. Elucidation of those genes that are differentially expressed between undifferentiated prostate cancer cells and prostate cancer cells that have been induced to differentiate may present new insights into the molecular mechanisms governing NE differentiation, early detection of prostate cancer, and potential targets for gene therapy. In this study, differential display polymerase chain reaction (PCR) was used to identify 226 differentially expressed PCR products. Twelve of the differential display PCR products were confirmed by Northern blot analysis and were cloned. DNA sequencing and database comparisons were performed. To our knowledge, this is the first report of the use of differential gene expression techniques to analyze gene expression during cAMP-induced NE differentiation in LNCaP cells. Confirmation of NE differentiation reversibility also was accomplished.
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PMID:Identification of differentially expressed genes during cyclic adenosine monophosphate-induced neuroendocrine differentiation in the human prostatic adenocarcinoma cell line LNCaP. 1181 1

It has been shown that expression of the RIalpha subunit of cyclic AMP (cAMP)-dependent protein kinase is enhanced in human cancer cell lines, primary tumors, and cells after transformation. Using an antisense strategy, we have shown that RIalpha has a role in neoplastic cell growth in vitro and in vivo. In the present study, we have investigated the sequence- and target-specific effects of exogenous RIalpha antisense oligodeoxynucleotides (ODNs) and endogenous antisense gene on tumor growth, apoptosis, and cAMP signaling in androgen-insensitive prostate cancer cells, both in vitro and in nude mice. Here, we show that an RIalpha antisense, RNA/DNA mixed backbone ODN exerts a reduction in RIalpha expression at both the mRNA and protein levels, up-regulation of both the RIIbeta subunit of cAMP-dependent protein kinase or protein kinase A and c-AMP-phosphodiesterase IV expression, and inhibition of cell growth. Growth inhibition was accompanied by changes in cell morphology and the appearance of apoptotic nuclei. In addition, Bcl-2 hyperphosphorylation; increase in the proapoptotic proteins Bax, Bak, and Bad; and Bad hypophosphorylation occurred in the antisense-treated cells. These effects of exogenously supplied antisense ODN mirrored those induced by endogenous antisense gene overexpression. The RIalpha antisense ODNs, which differed in sequence or chemical modification, promoted a sequence- and target-specific reduction in RIalpha protein levels and inhibited tumor growth in nude mice. These results demonstrate that in a sequence-specific manner, RIalpha antisense, via efficient depletion of the growth stimulatory molecule RIalpha, induces growth inhibition, apoptosis, and phenotypic (cell morphology) changes, providing an innovative approach to combat hormone-insensitive prostate cancer cell growth.
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PMID:Protein kinase A RIalpha antisense inhibition of PC3M prostate cancer cell growth: Bcl-2 hyperphosphorylation, Bax up-regulation, and Bad-hypophosphorylation. 1183 45

The importance of an early pharmacological prophylaxis for erectile function following nerve-sparing radical prostatectomy has been recently stressed by several authors. In spite of that, patient's compliance to erectile rehabilitation protocols seems to be low. The present review is an attempt to define the expected benefits of the currently proposed rehabilitative protocols in terms of cost-efficiency and quality of life. The conclusion is that current scientific evidence in support of an early postoperative use of erectile aids is based mainly on indirect proof of a cavernosal damage that may follow the temporary postoperative 'erectile silence'. Intracavernosal injections or a vacuum device may represent the best first-line treatment option for the first few months from the procedure as their mechanism of action does not require intact neural tissue for erection. Thereafter oral phosphodiesterase 5 inhibitor therapy may be a reasonable choice for those patients who can achieve at least a partial erection. A phosphodiesterase 5 inhibitor may not be effective when spontaneous erections are absent. It is possible, since the rehabilitation of sexual function aims to prevent cavernosal tissue damage by providing oxygenation to the erectile tissue, the choice of a potentially ineffective treatment may jeopardize the results of a reasonable nerve-sparing procedure.
Prostate Cancer Prostatic Dis 2004
PMID:Proerectile pharmacological prophylaxis following nerve-sparing radical prostatectomy (NSRP). 1524 31

Development in the management of prostate cancer has placed increased attention on patient quality of life after treatment, particularly sexual function. The incidence of erectile dysfunction (ED) in men following radical prostatectomy has been estimated to range from 16% to 82%. Several factors determine the postoperative incidence of erectile difficulties; these include patient age, degree of cavernosal nerve sparing during surgery, cancer stage, and associated comorbidities. Early initiation of available treatments after radical prostatectomy, such as phosphodiesterase-5 (PDE-5) inhibitors and intracavernosal alprostadil, may improve the speed and degree of recovery of erectile function. Oral PDE-5 inhibitors are recognized as the first line of therapy for men with ED after radical prostatectomy, with reasonable success rates reported for all commercially available PDE-5 inhibitors. In recognition of the neurogenic basis for erectile dysfunction after radical prostatectomy, new strategies have been devised, such as cavernous nerve graft interposition procedures, perioperative neuroprotection measures, and postoperative neurotrophic treatments. Hopefully, these efforts will improve quality of life for patients with prostate cancer. The aim of this article is to review the current modalities of ED management for men with prostate cancer.
Clin Prostate Cancer 2004 Sep
PMID:Current concepts in the management of erectile dysfunction in men with prostate cancer. 1547 91

Erectile dysfunction (ED) affects up to 50% of men, between 40 and 70 years of age. In the first major trial of sildenafil in ED, at 24 weeks, improved erections were reported by 77 and 84% of men taking sildenafil 50 and 100mg, respectively. Subsequently, sildenafil has been reported to be effective in men with ED associated with diabetes and prostate cancer, and in psychogenic ED. Sildenafil is safe in men with coronary artery disease, provided it is not used with the nitrates (a contraindication). The most commonly reported adverse effects with sildenafil are headache, flushing and dyspepsia. Vardenafil is more potent and more selective than sildenafil at inhibiting phosphodiesterase-5. Vardenafil is similarly effective to sildenafil in the treatment of ED. The only advantage that vardenafil has over sildenafil is that it does not inhibit phosphodiesterase-6 to alter colour perception, a rare side effect which sometimes occurs with sildenafil. Tadalafil has a longer duration of action than sildenafil and vardenafil. Tadalafil is similarly effective as sildenafil in the treatment of ED. In comparison studies, tadalafil is preferred to sildenafil (50/100mg) by men with ED, possibly because of its longer duration of action. Of the phosphodiesterase inhibitors, tadalafil may displace sildenafil as the drug of choice among men with ED.
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PMID:Comparison of clinical trials with sildenafil, vardenafil and tadalafil in erectile dysfunction. 1570 77

Cyclic nucleotide levels are controlled through their synthesis from nucleotide triphosphates by cyclases and their degradation to 5'-monophosphates by phosphodiesterases (PDEs). Components controlling cyclic AMP-induced relaxation in the urinary tract include receptors, inhibitory and stimulatory G-proteins, isoforms of adenylyl cyclase and PDEs. The responsiveness of PDEs to a variety of physiological challenges is related to the presence of multiple families of isoenzymes with specific localization within tissues and within cells. At least 11 families of PDEs encode more than 50 PDE proteins produced in mammalian cells. In the urinary tract, characterization of PDE isoforms has lagged behind other systems and much of the literature was published prior to identification of PDE7, 8, 9, 10, 11. Specific PDE inhibitors regulate smooth muscle function in the bladder, urethra, prostate and ureter. The pharmacological potential of these inhibitors may include treatment of urge incontinence and the low compliance bladder, and treatment of prostate cancer. G-proteins also regulate cyclic AMP production. Changes in specific G- protein isoforms with aging, most prominently Gialpha2, cause decreased relaxation response in the aging bladder. As we have seen here with aging and certainly in other disease processes, levels of the components of adenylyl cyclase/phosphodiesterase/protein kinase can change and thus affect the relaxation response. By exploitation of differences in PDE expression in disease, such as the overexpression of PDEs in cancer, treatment options may present themselves.
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PMID:Regulation of cyclic nucleotides in the urinary tract. 1585 36

Inhibition of phosphodiesterase-5 (PDE5) reduces the degradation of cyclic guanosine monophosphate, which allows erectile function to occur by relaxation of penile smooth muscle. Three PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) in a range of doses are available. PDE5 therapy, compared with placebo, significantly improves scores on the International Index of Erectile Function and has been found to be effective in special clinical populations, such as those with prostate cancer, diabetes, and cardiovascular disease. Sildenafil and vardenafil show some interaction with food intake. Time to onset of action is usually 30-120 minutes, but there are reports of shorter times to onset of action. The duration of action of sildenafil and vardenafil is about 4 hours, whereas that of tadalafil is about 36 hours. The overall safety of the treatments is good, even in patients with a history of cardiovascular disease. However, there is a risk of hypotension if nitrates are given concurrently. Increased QTc intervals have been reported, the longest with vardenafil, shortest with tadalafil, and intermediate with sildenafil. Priapism and prolonged erection are rare adverse events. Common side-effects include headache, facial flushing, nasal congestion, and dyspepsia. There may be interactions with other medications metabolized in a similar way, such as erythromycin and HIV protease inhibitors.
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PMID:The efficacy and safety of PDE5 inhibitors. 1615 23


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