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)

The efficacy of Casodex (ICI 176,334; Zeneca Pharmaceuticals, Macclesfield, UK), a nonsteroidal antiandrogen, in the treatment of advanced prostate cancer has been compared in two trials with castration, either surgical (bilateral orchitectomy) or medical, with the gonadotropin-releasing hormone agonist Zoladex (goserelin acetate; Zeneca Pharmaceuticals). The half-life of Casodex is 7 to 10 days, and allows once-daily dosing. The first trial was a prospective, randomized study involving 150 patients receiving Casodex, 50 mg once daily p.o., and 154 patients undergoing castration. There were no significant differences between the two groups in subjective responses, time to treatment failure, or time to objective evidence of disease progression. The other study involved higher doses, the dose being selected after patients had received one of two doses of Casodex, 100 mg/day or 150 mg/day, in a double-blind study. On statistical analysis, it was clear that the higher dose was more effective, and thus most patients taking 100 mg/day were switched to 150 mg/day. Again, Casodex treatment was compared with medical or surgical castration. The higher dose of Casodex is well tolerated with a similar adverse event profile as the lower dose of 50 mg/day. Follow-up is as yet too short for an analysis of efficacy.
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PMID:Current clinical studies with a new nonsteroidal antiandrogen, Casodex. 817 13

As a first effort to introduce quality-of-life assessment in prostatic cancer clinical trials, the European Organization for Research and Treatment of Cancer Genitourinary Group, in cooperation with European Organization for Research and Treatment Quality of Life Group, initiated protocol 30853, coordinated by Louis Denis. This protocol compared the efficacy of treatment with orchiectomy alone to that with Zoladex (Zeneca Pharmaceuticals, Alderley Macclesfield, Cheshire, UK) plus flutamide in previously untreated patients with metastatic cancer. The use of patient-administered quality-of-life questionnaires was optional, and of 327 patients, only 22% had pretreatment assessments. This trial revealed many clinician's considerable reluctance to perform quality of life research, partly because of feasibility problems and partly because of doctors' doubts about the value of such efforts. Psychologic distress, fatigue, issues of social and family life, and pain were found to be the most important concerns on a subjective basis, and this finding was confirmed by objective parameters. There was a discrepancy between doctors' evaluations and patients' opinions about subjective morbidity, namely sexual status and pain. Quality of life assessment should become a mandatory part of clinical trials in prostate cancer.
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PMID:Quality of life in prostatic cancer patients. 825 94

A total of 327 patients with metastatic prostate cancer were randomized to receive bilateral orchiectomy or treatment with Zoladex and flutamide. The trial aimed to evaluate subjective and objective time to progression, survival, and incidence and duration of response. Strict quality control and evaluation by independent ad hoc committees were organized. Progression was assessed for each of 13 parameters. The time to subjective and objective progression was in favor of the combination treatment, with statistical significances of P = 0.009 and P = 0.008, respectively. This delay in objective progression resulted in increased survival in favor of the combination treatment for death by cancer (P = 0.02) or overall survival (P = 0.05). Survival differences were more marked in the patients with better prognostic factors. The clinical significance of these differences for the individual patient requires detailed assessment.
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PMID:Orchidectomy versus goserelin plus flutamide in patients with metastatic prostate cancer (EORTC 30853). European Organization for Research and Treatment of Cancer--Genitourinary Group. 825 5

Casodex (Bicalutamide, ICI 176,334) is a potent, non-steroidal, selective anti-androgen with a long half-life allowing once-daily oral administration. In this randomised, open, multicentre study, Casodex 50 mg monotherapy was compared with castration (medical, using goserelin acetate, [Zoladex], or surgical) in 245 patients with advanced prostate cancer. Primary end-points were time to treatment failure, time to objective progression and survival. Subjective responses, quality of life and tolerability were also evaluated. There was no significant difference between the groups in terms of objective progression or subjective responses. Treatment failed in 59 of 119 patients (50%) randomised to Casodex and in 61 of 126 patients (48%) randomised to castration (no statistically significant difference). An updated analysis showed that survival was similar in the two groups. Casodex was well tolerated with a low incidence of diarrhoea and sexual dysfunction. On the basis of this study, Casodex monotherapy is an effective alternative to castration in the treatment of metastatic prostate cancer.
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PMID:A randomised comparison of monotherapy with Casodex 50 mg daily and castration in the treatment of metastatic prostate carcinoma. Casodex Study Group. 853 75

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

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

A prospective randomised study was performed to test the hypothesis that total androgen ablation, achieved by combining an LHRH analogue, goserelin acetate (Zoladex), with an antiandrogen, cyproterone acetate (Cyprostat), is more effective than conventional monotherapy in delaying the time to progression of metastatic prostatic cancer. 525 patients were recruited at 18 UK centres between May 1986 and January 1989, 175 patients being allocated to each arm. Patients were clinically and biochemically assessed at 1, 2, 3, 6, 9 and 12 months after initiation of therapy and then every 6 months until a maximum duration of 48 months. There was no statistically significant difference in terms of median time to progression between the combination treatment arm and either monotherapy arm, although there was a statistically significant difference between goserelin acetate alone and cyproterone acetate alone, in favour of goserelin acetate (p = 0.016). All treatment regimens were well tolerated and cyproterone acetate reduced both tumour flare reactions and hot flushes in patients receiving goserelin acetate. It is concluded that total androgen ablation using cyproterone acetate (300 mg/day) and goserelin acetate (3.6 mg every 28 days) confers no advantage in terms of time to progression, to conventional monotherapy, but can reduce certain side effects caused by LHRH analogue treatment alone.
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PMID:A prospective, randomised study to compare goserelin acetate (Zoladex) versus cyproterone acetate (Cyprostat) versus a combination of the two in the treatment of metastatic prostatic carcinoma. 882 90

LH-releasing hormone (LHRH) agonists exert a direct inhibitory action on the growth of both androgen-dependent (LNCaP) and androgen-independent (DU 145) human prostatic cancer cell lines. The present studies were aimed at clarifying whether these compounds might exert their antiproliferative action by interfering with the stimulatory action of epidermal growth factor (EGF). To this purpose, the effects of a LHRH agonist (Zoladex, LHRH-A) on the mitogenic action of EGF, on some of the EGF-activated intracellular signaling mechanisms (tyrosine phosphorylation of the 170-kDa EGF receptor, and c-fos protooncogene expression), as well as on the concentration of EGF receptors have been evaluated. These studies have been performed in both LNCaP and DU 145 cells. The results obtained show that in LNCaP cells, LHRH-A counteracts the mitogenic action of EGF, completely abrogates EGF-induced c-fos expression, and significantly reduces the concentration of EGF-binding sites. The EGF-activated tyrosine phosphorylation of the EGF receptor is not affected by LHRH-A in LNCaP cells. In DU 145 cells, LHRH-A antagonizes the proliferative action of EGF, inhibits the tyrosine phosphorylation of the EGF receptor induced by EGF, and significantly reduces the number of EGF-binding sites. In these cells, LHRH-A is not able to modify the increased expression of c-fos that follows the treatment with EGF. These data suggest that LHRH agonists may inhibit the proliferation of human prostatic tumor cells by interfering with the stimulatory actions of EGF. The intracellular mechanism of action of these compounds appears to differ in androgen-dependent LNCaP and androgen-independent DU 145 cells.
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PMID:Luteinizing hormone-releasing hormone agonists interfere with the stimulatory actions of epidermal growth factor in human prostatic cancer cell lines, LNCaP and DU 145. 892 40

40 male patients with metastatic prostate cancer given a choice of medical castration with the LHRH Analogue Goserelin (Zoladex) or surgical castration chose medical treatment. During a 15 month follow up only one patient decided to have an orchidectomy and this was because of treatment expense.
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PMID:Patient treatment preference in metastatic prostate cancer. 898 72

Luteinizing Hormone Releasing Hormone (LHRH) agonists exert both "in vitro" and "in vivo" a direct inhibitory action on the growth of both androgen-dependent (LNCaP) and androgen-independent (DU 145) human prostatic cancer cell lines. The present experiments have been performed to investigate the mechanisms involved in this direct antiproliferative action of LHRH agonists. In particular, the aim was to study whether these compounds might exert their antiproliferative effect by interfering with the stimulatory action of epidermal growth factor (EGF) both "in vitro" and "in vivo". To this purpose, the effects of LHRH agonist, Zoladex (LHRH-A), on the mitogenic action of EGF, on EGF-activated intracellular signaling mechanisms (tyrosine phosphorylation of EGF receptor and c-fos proto-oncogene expression), and on the concentration of EGF receptors have been evaluated in both LNCaP and DU 145 cells. The results of these "in vitro" studies show that in LNCaP cells LHRH-A counteracts the mitogenic action of EGF, abrogates the EGF-induced c-fos expression and reduces the concentration of EGF-binding sites, without modifying the EGF induced tyrosine phosphorylation. In DU 145 cells, LHRH-A antagonizes the proliferative action of EGF, inhibits tyrosine phosphorylation of EGF receptor induced by EGF and significantly reduces the number of EGF binding sites, without altering the stimulation of c-fos expression induced by EGF. For the "in vivo" experiments, male nude mice were s.c. injected in the flank with DU 145 cells and treated for 14 days with LHRH-A (100 micrograms/days). At the end of the treatment, the concentration of EGF receptors on membrane preparations as well as on tumor volume were found to be significantly lower in LHRH-A treated animals than in control mice. The mitotic index and the expression of the proliferation-associated antigen Ki67 were found similar in control as well as in treated animals. In addition no modification of apoptotic index (expression of p53) was observed. These data suggest that LHRH agonists may inhibit the proliferation of the tumor cells by interfering with the stimulatory actions of EGF.
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PMID:Effects of LHRH agonists on the growth of human prostatic tumor cells: "in vitro" and "in vivo" studies. 939 87


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