Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accumulated epidemiological evidence indicates that prostate cancer mortality should be preventable. As androgenic hormones have long been recognised to be required for normal prostatic development, and because androgen deprivation is an established treatment for advanced prostate cancer, androgen signalling has been an attractive target for prostate cancer prevention. Inhibitors of 5alpha-reductase, an enzyme necessary for the conversion of testosterone to the more potent androgen dihydrotestosterone, have reached pivotal clinical trials for prostate cancer prevention. In addition, new insights into the molecular pathogenesis of prostate cancer hint that chronic or recurrent prostate inflammation may contribute to the development of the disease. A variety of antioxidants and anti-inflammatory drugs, which are likely to be capable of attenuating pro-carcinogenic genome damage from reactive oxygen and nitrogen species, are also under current development for prostate cancer prevention. This review will consider the rational development of these and other new agents and approaches for prostate cancer prevention in the context of recent research progress in ascertaining the aetiology of prostate cancer.
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PMID:Agents in development for prostate cancer prevention. 1600 79

The prostate has only one function, namely to secrete fluid containing substances that are needed for reproduction. This requires an extremely high concentration of androgens in the tissues. Benign prostatic hypertrophy (BPH) seems to be related to the long-term exposure of the prostate to the strong androgen 5alpha-dihydrotestosterone (DHT) and, possibly, to estrogens. The relation between prostate cancer and androgens is suggested to be U-shaped, with both extremes of androgen concentrations being associated with increased risk of invasive cancer. In the treatment of patients with BPH, the lipidic liposterolic extracts of Serenoa repens were as effective as the pharmaceutical inhibitors of the 5alpha-reductase enzyme or alpha1-adrenergic blockers in relieving urinary symptoms. In addition to moderately inhibiting the 5alpha-reductase activity, Serenoa seems to exert anti-inflammatory and complementary cellular actions with beneficial effects on the prostate. Unlike the pharmaceutical 5alpha-reductase inhibitors, finasteride and dutasteride, Serenoa does not suppress serum PSA, facilitating the follow-up and the early detection of prostate cancer. We suggest a strategy to prevent prostate cancer that aims at providing men with partial androgen deficiency correct testosterone substitution with a sustained release buccal bio-adhesive tablet. In addition, food supplementation with extracts of Serenoa repens and a combination of the antioxidants selenium, (cis)-lycopene and natural vitamin E, together with fish oil rich in long-chain polyunsaturated essential fatty acids of the omega-3 group seems warranted. Clearly, a holistic approach including careful clinical and biological monitoring of the aging man and his prostate remains mandatory.
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PMID:Preventing diseases of the prostate in the elderly using hormones and nutriceuticals. 1567 40

Dutasteride is a new dual 5alpha-reductase inhibitor for the treatment of benign prostatic hyperplasia. It differs from finasteride as it inhibits both isoenzymes of 5alpha-reductase and results in near-complete suppression of serum dihydro-testosterone. Similar to finasteride, it reduces serum prostatic specific antigen by approximately 50% at 6months and total prostate volume by 25% in 2years. Randomised, placebo-controlled trials conducted over 2years have shown the efficacy of dutasteride in symptomatic relief, improvements in quality of life and peak urinary flow rate, and reduction of acute urinary retention events and the need for surgery. The main side effects are erectile dysfunction, decreased libido, gynaecomastia and ejaculation disorders. However, long-term usage for > 4years did not reveal increased new onset of sexual side effects. In addition, the combination of dutasteride and tamsulosin is well-tolerated and has the added advantage of rapid symptomatic relief. Finally, dutasteride has been shown to possess tumour regression properties invitro and its role in chemoprevention of prostate cancer will be confirmed in the ongoing Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial.
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PMID:Dutasteride: a novel dual inhibitor of 5alpha-reductase for benign prostatic hyperplasia. 1575 26

The enzyme 5alpha-reductase is responsible for the conversion of testosterone (T) to its more potent androgen dihydrotestosterone (DHT). This steroid had been implicated in androgen-dependent diseases such as: benign prostatic hyperplasia, prostate cancer, acne and androgenic alopecia. The inhibition of 5alpha-reductase enzyme offers a potentially useful treatment for these diseases. In this study, we report the synthesis and pharmacological evaluation of several new 3-substituted pregna-4, 16-diene-6, 20-dione derivatives. These compounds were prepared from the commercially available 16-dehydropregnenolone acetate. The biological activity of the new steroidal derivatives was determined in vivo as well as in vitro experiments. In vivo experiments, the anti-androgenic effect of the steroids was demonstrated by the decrease of the weight of the prostate gland of gonadectomized hamster treated with T plus finasteride or the new steroids. The IC50 value of these steroids was determined by measuring the conversion of radio labeled T to DHT. The results of this study carried out with 5alpha-reductase enzyme from hamster and human prostate showed that four of the six steroidal derivatives (5, 7, 9, 10) exhibited much higher 5alpha-reductase inhibitory activity, as indicated by the IC50 values than the presently used Proscar 3 (finasteride). The comparison of the weight of the hamster's prostate gland indicated that compound 5 had a comparable weight decrease as finasteride. The overall data of this study showed very clearly those compounds 5, 7, 9, 10 are good inhibitors for the 5alpha-reductase enzyme.
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PMID:New 5alpha-reductase inhibitors: in vitro and in vivo effects. 1576 1

Androgens have been proposed to be actively produced in situ in human prostate cancer. These locally produced androgens have also been considered to play important roles in the pathogenesis and development of prostate cancer. Therefore, it is important to examine the status of this in situ androgen metabolism and/or synthesis in detail in order to improve the clinical response to hormonal therapy in patients diagnosed with prostate cancer. Several studies have previously demonstrated the expression of androgen-producing enzymes such as 5alpha-reductase types 1 and 2, and 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD5), in human prostate carcinoma cells. However, their biological significance has remained largely unknown. In this study, we evaluated the immunoreactivities of these steroidogenic enzymes in human prostate cancer obtained from surgery (n = 70), and correlated the findings with clinicopathological features of the patients. 17Beta-HSD5 immunoreactivity was detected in 54 cases (77%), 5alpha-reductase type 1 in 51 cases (73%) and 5alpha-reductase type 2 in 39 cases (56%). 5Alpha-reductase type 2 immunoreactivity was significantly correlated with that of androgen receptor (AR), and 17beta-HSD5 positive cases were significantly associated with clinical stage (TNM stage pT3 vs pT2). These data all suggest that androgen-producing enzymes, such as 5alpha-reductase type 1 and type 2, and 17beta-HSD5 are expressed in a majority of prostate cancers, and are involved in the local production and actions of androgens in prostate cancers.
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PMID:In situ androgen producing enzymes in human prostate cancer. 1578 42

Human 5alpha-reductase catalyses the last step in androgen biosynthesis, namely the reduction of testosterone (T) to the more potent androgen dihydrotestosterone (DHT). The enzyme is therefore considered to be an important drug target for androgen related diseases such as benign prostatic hyperplasia and prostate cancer. The present study displays evidence that the human embryonic kidney cell line HEK293 which is frequently used in recombinant target protein expression contains an endogenous 5alpha-reductase type II activity. After an incubation of 24 h 1 x 10(6) HEK293 cells converted 23% of the substrate 4-androstene-3,17-dione (7.5 nM) to the product 5alpha-androstane-3,17-dione. Reverse transcription polymerase chain reaction was carried out to identify the mRNA of the isoform responsible for the 5alpha-reductase activity. Only with type II specific primers a fragment with the predicted size was amplified, while with type I specific primers no band could be observed. An antiserum against human 5alpha-reductase type II was raised by immunizing a rabbit with a hemocyanin-conjugated peptide corresponding to amino acid 29 to 44 of the type II enzyme. Western blot analysis of different fractions of a HEK293 homogenate performed with this antiserum detected a band at 45 kDa in the nuclear and microsomal fraction corresponding to 5alpha-reductase type II protein.
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PMID:5alpha-reductase in human embryonic kidney cell line HEK293: evidence for type II enzyme expression and activity. 1579 68

5alpha-Reductase inhibitors and alpha(1)-receptor blockers are established options for symptomatic treatment of benign prostatic hyperplasia (BPH). Achieving maximum efficacy is contingent on correct dosage and requires careful patient selection in view of the substance class employed. All applicable preparations exert only a low-grade effect on prostatic obstruction. This condition should be excluded by appropriate urological examination before treatment is initiated. If the patient's distress is minor, refraining from drug therapy can be considered. Symptomatic patients with small prostate volume are suited for monotherapy with alpha(1)-receptor blockers and symptomatic patients with large prostate volume profit from combination therapy. When 5alpha-reductase inhibitors are used, BPH patients should be made aware of the findings from the Prostate Cancer Prevention Trial.
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PMID:[Drug therapy for benign prostatic hyperplasia. Systematic overview]. 1584 55

Estrogens and androgens are proposed to play a role in the pathogenesis of prostate cancer. The effective metabolites, estradiol and 5alpha-dihydrotestosterone are produced from testosterone by aromatase and 5alpha-reductase, respectively. Metabolites of vitamin D have shown to inhibit the growth of prostate cancer cells. The aim of the present study was to verify whether 25-hydroxyvitamin D(3) (25OHD(3)), 1alpha,25-dihydroxyvitamin D(3) [1alpha,25-(OH)(2)D(3)], dexamethasone, and progesterone regulate the expression of aromatase and 5alpha-reductase in human prostate cancer cells. LNCaP and PC3 cells were treated with 25OHD(3), 1alpha,25-(OH)(2)D(3), dexamethasone, or progesterone. Aromatase and 5alpha-reductase mRNA was quantified by real-time RT-PCR and aromatase enzyme activity was measured by the [(3)H] water assay. Aromatase enzyme activity in LNCaP and PC3 cells was increased by both 10nM dexamethasone, 1-100 nM 1alpha,25-(OH)(2)D(3) and 100 nM-10 microM progesterone. The induction was enhanced when hormones were used synergistically. Real-time RT-PCR analysis showed no regulation of the expression of aromatase mRNA by any steroids tested in either LNCaP or PC3 cells. The expression of 5alpha-reductase type I mRNA was not regulated by 1alpha,25-(OH)(2)D(3) and no expression of 5alpha-reductase type II was detected in LNCaP.
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PMID:Regulation of aromatase and 5alpha-reductase by 25-hydroxyvitamin D(3), 1alpha,25-dihydroxyvitamin D(3), dexamethasone and progesterone in prostate cancer cells. 1586 60

Prostate cancer has been one of the most frequent cancers among men in Western countries for the past decade. Investigation of prostate cancer prevention is very attractive, because prostate cancer has a high incidence, long-term natural history, regional difference in incidence, and is effected by sex steroids. Chemoprevention is defined as the use of specific agents to suppress or reverse carcinogenesis and to prevent the development of cancer. The development of chemoprevention strategies against prostate cancer would be of medical and economic importance. Basic and clinical research of chemoprevention of prostate cancer are under active investigation. This article aims to summarize and review the basic evidence and clinical trials on prostate cancer chemoprevention. Recent research has demonstrated that many agents, such as agents altering sex steroid signaling, drugs inducing antiproliferation/differentiation, retinoids, anti-inflammatory drugs, and antioxidants, could be potential preventatives for prostate cancer. Large-scale clinical trials have suggested that 5alpha-reductase inhibitor finasteride, selenium, and vitamin E can function as a chemopreventive agent. Although no definitely effective strategies of prostate cancer prevention have been identified yet, increasing evidence will provide effective and safe strategies that bring clinical benefits.
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PMID:Can we prevent prostate cancer? Rationale and current status of prostate cancer chemoprevention. 1589 91

A promising liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) for analysis of the sulfates of 5alpha-androgen, androsterone and epiandrosterone (A-S and EpiA-S) in human serum was developed. The method was used to assess one of the markers of 5alpha-reductase activity of males including patients with prostate cancer (PC). After deproteinization with acetonitrile, the androgen sulfates and the internal standard, [7,7,16,16-2H4]dehydroepiandrosterone-S, were extracted from human serum using a solid-phase extraction cartridge and washed with hexane. The extract was reconstituted and applied to the LC/ESI-MS system operated in the selected ion monitoring mode. The method was validated over the range 0.02-5 microg/mL (A-S) and 0.005-1.5 microg/mL (EpiA-S) using 10 microL of human serum. The method was a concise procedure without chemical or enzymatic hydrolysis of the conjugates, purification by high-performance liquid chromatography and/or derivatization, and proved to be satisfactory in its reproducibility and accuracy. The levels of these androgen sulfates tended to decrease during aging, and the A-S levels in the sera obtained from both healthy males and patients with PC were correlated with their EpiA-S levels.
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PMID:Determination of sulfates of androsterone and epiandrosterone in human serum using isotope diluted liquid chromatography-electrospray ionization-mass spectrometry. 1595 57


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