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)

To investigate the efficacy and safety of bicalutamide (Casodex) with its clinically recommended dose, the randomized early phase II study was performed in 124 patients with prostatic cancer (stage C, D). The patients were given 50, 80 or 100 mg of bicalutamide orally once a day in fixed doses for 12 weeks; 122 patients were eligible for evaluation. The overall response rate was 50.0% (20/40), 61.0% (25/41) and 53.7% (22/41) in the 50 mg, 80 mg and 100 mg groups, respectively. The response rate in prostate lesion, bone and lymph node metastases was slightly higher in the 80 mg group than in the 50 mg and 100 mg groups. The proportion of patients showing a response with regard to serum PSA (CR and PR) was 84.2, 92.7 and 97.6% in the 50, 80 and 100 mg groups, respectively. The incidence of adverse reactions was 65.0, 61.0 and 61.0% in the 50, 80 and 100 mg groups, respectively, and there was no significant difference in overall safety rating in the three groups. Frequent adverse reactions were gynecomastia and breast pain. Only one patient in the 80 mg group was withdrawn due to shortness of breath. Serum concentrations of LH, testosterone and estradiol increased significantly after treatment. Bicalutamide was concluded to be effective and well tolerated in patients with prostatic cancer, and its recommended dose was 80 mg once daily.
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PMID:[Clinical early phase II study of bicalutamide (Casodex) in patients with prostatic cancer]. 871 92

Casodex (bicalutamide, Zeneca Limited) was developed for the treatment of prostate cancer from a series of nonsteroidal compounds related to flutamide. Casodex is a selective antiandrogen that binds to rat, dog and human prostate androgen receptors, and has approximately a 4-fold higher affinity for the rat androgen receptor than hydroxyflutamide, the active metabolite of flutamide. Casodex also binds to androgen receptors found in the LNCaP human prostate tumour and the Shionogi S115 mouse mammary tumour cell line, as well as androgen receptors transfected into CV-1 and HeLa cells. In all cases, Casodex behaves as a 'pure' antiandrogen and inhibits gene expression and cell growth stimulated by androgens. Studies in vivo show that Casodex is a potent antiandrogen in the rat. In contrast to flutamide, which produces dose-related, marked increases in serum luteinising hormone (LH) and testosterone, Casodex has little effect on serum LH and testosterone; that is, it is peripherally selective. The peripheral selectivity of Casodex has now been shown to be due to poor penetration across the blood-brain barrier. In dogs, Casodex has exquisite potency and causes dose-related atrophy of the prostate gland and epididymis; with an oral ED50 of 0.1 mg/kg, it is about 50 times as potent as flutamide in this species. Casodex is also peripherally selective in the dog. In addition, magnetic resonance imaging studies have shown that Casodex is a potent antiandrogen in the monkey. Casodex, at a daily oral dose of 25 mg/kg effected a highly significant reduction in the growth of Dunning R3327H transplantable rat prostate tumours that was equivalent to that achieved by either surgical or medical castration with the LH-releasing hormone agonist Zoladex (goserelin). In a comparative study, flutamide was shown to be both less potent and less active than Casodex. In these preclinical studies, Casodex was well tolerated. The preclinical properties of Casodex give it advantages, with respect to potency, tolerability and the maintenance of effective antiandrogen serum concentrations, over other available antiandrogens. Moreover, it has a half-life that is compatible with once-daily administration.
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PMID:The development of Casodex (bicalutamide): preclinical studies. 871 69

Casodex (bicalutamide, Zeneca Limited) is a nonsteroidal competitive inhibitor of androgens at the androgen receptor. The drug was developed to fulfil a number of needs for the treatment of prostate cancer. The specific aim was to demonstrate pharmacological activity, which would translate into clinical efficacy, good tolerability in the context of its use, oral availability, a convenient and forgiving dosing regimen, and clinical acceptability. Casodex has been shown to be orally bioavailable and well absorbed, with a plasma half-life of around 1 week. Although steady-state levels are not reached for 1 month, there is evidence that the androgen receptor blockade achieved with Casodex is equivalent to that of flutamide by the end of the first day. The dose of Casodex was established in a series of dose-ranging studies using the surrogate endpoints of prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA). Initial studies suggested that a dose of 50 mg daily gave a fall in PAP equivalent to that seen with castration. This dose was, therefore, evaluated as monotherapy and subsequently as a component of combined androgen blockade. Higher doses were evaluated using PSA as a surrogate endpoint and, although doses up to 450 mg have been given to man, 150 mg daily is well tolerated with demonstrable evidence of activity. Although trials of the drug at 150 mg in monotherapy have, to date, not shown survival equivalence with castration, Casodex has been well tolerated with evidence of good symptomatic response and quality-of-life benefits including the potential of retaining libido. In combination treatment, Casodex is associated with significantly less gastrointestinal effects (diarrhoea) than the nonsteroidal antiandrogen flutamide (Eulexin, Schering-Plough International). Casodex is not associated with alcohol intolerance, pneumonitis and ocular defects which have been seen with the antiandrogen nilutamide (Anandron, Roussel). Moreover, since Casodex is a nonsteroidal antiandrogen, no steroidal effects have been seen.
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PMID:Clinical progress with a new antiandrogen, Casodex (bicalutamide). 871 70

Between January 1992 and September 1993, 813 patients with stage D2 prostate cancer were enrolled in a multicentre, double-blind (for antiandrogen therapy) trial and randomised to antiandrogen therapy with Casodex (bicalutamide, 50 mg once daily) or flutamide (250 mg three times daily) and to luteinising hormone-releasing hormone (LHRH) analogue therapy with Zoladex (goserelin, 3.6 mg every 28 days) or leuprolide (7.5 mg every 28 days). Time to treatment failure was the primary efficacy endpoint. At a median follow-up time of 49 weeks, there was a significant (p = 0.005) difference between groups in time to treatment failure in favour of Casodex plus LHRH analogue. Overall, 168 (42%) of 404 patients in the Casodex plus LHRH analogue group and 218 (53%) of 409 patients in the flutamide plus LHRH analogue group reached a treatment failure endpoint. Although a cause-specific treatment-failure analysis was not performed, the difference between groups in treatment failure attributed to adverse events (mainly diarrhoea) was evident primarily in the first 7 months of therapy. The difference between groups in treatment failure for objective progression was most evident after 1 year of therapy. With further follow-up (median time of 95 weeks), the result for time to treatment failure, although no longer statistically significant, were consistent with the previous finding of an improvement in time to treatment failure associated with Casodex plus LHRH analogue therapy. With a median of 95 weeks of follow-up, 34% of deaths had occurred. The survival analysis was not dissimilar between the 2 groups. At 49 weeks median follow up, the incidence of diarrhoea was significantly (p < 0.001) lower among patients in the Casodex plus LHRH analogue group. Diarrhoea led to withdrawal from therapy for 2 patients in the Casodex plus LHRH analogue group, compared with 25 patients in the flutamide plus LHRH analogue group. In conclusion, Casodex plus LHRH analogue is well tolerated and effective with an improvement in time to treatment failure over flutamide plus LHRH analogue. Survival was not dissimilar between the 2 treatment groups.
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PMID:A controlled trial of Casodex (bicalutamide) vs. flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Casodex Combination Study Group. 871 71

The effect of Casodex (ICI 176,334), a new, once-daily, selective antiandrogen, given as 50 mg monotherapy, was compared with orchidectomy in a randomised, multicentre, open study in 376 patients with metastatic prostate cancer. At 3 months, PSA was reduced by 86% in the Casodex group and by 96% in the orchidectomy group. Treatment failed in 51 patients in the orchidectomy group and 66 showed a subjective response. Treatment failed in 86 patients treated with Casodex and 40 patients showed a subjective response. Patients treated with Casodex maintained their sexual interest better than those in the orchidectomy group. Median survival was significantly longer in the orchidectomy group. Casodex was well-tolerated. The most likely reason for the differences between the groups regarding time to treatment failure and survival is that the dose of Casodex was too small. Further studies with higher doses of Casodex are in progress.
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PMID:Randomised study of Casodex 50 MG monotherapy vs orchidectomy in the treatment of metastatic prostate cancer. The Scandinavian Casodex Cooperative Group. 873 52

The potential for hepatic enzyme induction by bicalutamide ('Casodex') was assessed in an open study in prostate cancer patients. A single, oral dose of antipyrine 1000 mg was given before and after 12 weeks' bicalutamide therapy [once daily 50 mg (n = 7) or 150 mg (n = 11)] and its pharmacokinetics and metabolism were determined. Plasma or saliva samples were taken for the measurement of antipyrine concentration. Urine samples were assayed for antipyrine and its three major metabolites. With bicalutamide 50 mg, plasma antipyrine concentrations were maximal between 2 and 4 h after administration, declined in a log-linear manner and were unaffected by bicalutamide therapy; with bicalutamide 150 mg, saliva antipyrine concentrations were maximal between 2 and 4 h, declined in a log-linear manner, and were also unaffected by bicalutamide therapy. Antipyrine half-life was 16.3% shorter after bicalutamide 50 mg (p < 0.05); a small decrease (13.5%) in half-life after bicalutamide 150 mg was not statistically significant. A small reduction (18.6%, p < 0.05) in the AUCinfinity for antipyrine was noted after bicalutamide 150 mg. A statistically significant reduction in antipyrine recovery was seen with the lower bicalutamide dose (23.7%, p < 0.05). The statistically significant changes were small in absolute terms and showed no dose-response relationship. Bicalutamide does not significantly induce the hepatic enzymes responsible for antipyrine metabolism and has no obvious potential for producing clinically significant drug interactions due to enzyme induction.
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PMID:Absence of hepatic enzyme induction in prostate cancer patients receiving 'Casodex' (bicalutamide). 874 99

Although much attention has been focused on the synthesis of dihydrotestosterone (DHT), the inactivation and elimination of active androgens can also be key points in regulating androgen levels in tissues such as the prostate. Recent data suggest that 5alpha-reduced C19 steroids can be converted to glucuronide derivatives in the human prostate, leading to complete inactivation of these steroids. These results are supported by the recent finding of at least two steroid uridine diphosphoglucuronosyltransferase (UGT) enzymes in the prostate as well as in the human prostatic cancer LNCaP cell line. To ascertain the role of UGTs in regulating active steroid levels, we investigated the modulation of UGT levels in response to steroid treatments in LNCaP cells. Results demonstrate the down-regulation of UGT activities specific for 3-hydroxysteroids and 17-hydroxy-steroids after treatment with androgens and estrogens. Treating the cells with DHT or R1881 for 7 days inhibited UGT activity by 60%; however, 80% of the total activity was recovered after 5 days in the absence of the androgens. The inhibition of UGT activities by DHT and R1881 increases with the time of incubation and with increasing concentrations of the androgens used. The decrease in UGT enzyme activity occurred in parallel with a diminution in UGT transcript levels, as observed in Northern blot analyses. A correlation between the effect of steroids on the androgen-dependent growth response of LNCaP cells, the secretion of prostate-specific antigen, and the inhibition of UGT activities was clearly demonstrated, which implicates the androgen signaling pathway. Treating cells with Casodex, an androgen antagonist that binds the mutated androgen receptor expressed in LNCaP cells, partially blocked the androgen- and estrogen-induced decrease in UGT activity, suggesting that the regulation of UGT levels involves the androgen receptor. In addition to the formation of DHT, the inactivation of steroids by glucuronidation, which is regulated by steroids themselves, is an important mechanism controlling the level of androgens in the prostate.
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PMID:Regulation of steroid glucuronosyltransferase activities and transcripts by androgen in the human prostatic cancer LNCaP cell line. 877 Sep 8

In addition to modulation of cell proliferation and stimulation of prostate-specific antigen secretion, one of the most striking effects of androgens on the human prostate cancer cell line LNCaP is the accumulation of neutral lipids. These lipids are synthesized de novo, suggesting that LNCaP cells express all enzymes required for endogenous lipogenesis and that the expression and/or activity of some of these enzymes is affected by androgens. One of the key enzymes involved in lipogenesis is fatty acid synthase (FAS), a potential prognostic enzyme and therapeutic target that is found to be frequently overexpressed in a variety of cancers including prostate cancer. Here, using Northern blot analysis, the gene encoding FAS is shown to be abundantly expressed in LNCaP cells and in two other prostate cancer cell lines tested (PC-3 and DU-145). In LNCaP cells, androgen treatment (10(-8) M R1881) causes a 3-4-fold increase in FAS mRNA levels. Concomitantly with the increase in FAS gene expression, androgens induce a 10-12-fold stimulation of FAS activity. Effects are dose- and time-dependent and follow courses similar to those of the androgen induction of lipid accumulation. In support of the involvement of the androgen receptor, steroid specificity of regulation of FAS activity is in agreement with the aberrant ligand specificity of the mutated androgen receptor in LNCaP cells. Stimulation of FAS activity is inhibited by the antiandrogen Casodex (bicalutamide) and is absent in the androgen receptor-negative cell lines PC-3 and DU-145. Taken together, these data demonstrate that androgens, mediated by the androgen receptor, stimulate the expression and activity of FAS and suggest that stimulation of FAS activity represents at least part of the mechanism by which androgens induce the accumulation of neutral lipids in LNCaP cells.
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PMID:Androgens stimulate fatty acid synthase in the human prostate cancer cell line LNCaP. 906 76

Evolving data suggest that palliation of relapsed prostate cancer can be achieved by the selective discontinuation of agents that act via steroid hormone receptors. Clinical benefit has been observed following the withdrawal of flutamide (Eulexin, Schering-Plough International), bicalutamide (Casodex, Zeneca Ltd), oestrogens, progestational agents and retinoids. For patients with progression of disease while receiving these drugs, a period of observation after withdrawal should be considered before further therapy is initiated.
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PMID:The antiandrogen withdrawal syndrome in relapsed prostate cancer. 907 3

The utility of monotherapy with antiandrogens in prostate cancer is under investigation. Flutamide (Eulexin, Schering-Plough International) appears equally effective to castration in prolonging progression-free survival. Nilutamide (Anandron, Roussel) has been studied less widely, but may represent a valid treatment option in advanced prostate cancer. Preliminary results suggest that bicalutamide (Casodex, Zeneca Ltd) is as effective as castration in non-metastatic disease. Monotherapy with non-steroidal antiandrogens may offer successful palliative management of advanced prostate cancer with significant value in enhancing certain aspects of quality of life.
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PMID:Antiandrogen monotherapy in the management of advanced prostate cancer. 907 6


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