Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0600139 (Prostate Cancer)
 4,540 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Highly potent LH-releasing hormone (LHRH) agonists have been recently introduced in therapy for the treatment of the carcinoma of the prostate, an androgen-dependent pathology. These peptides are believed to act mainly by inhibiting the pituitary-testicular axis and, consequently, by reducing testosterone levels. The recent observation that binding sites for LHRH analogs are present on prostatic tumor tissue suggests that these drugs could also act directly on the tumor. To verify this hypothesis, the effects of two potent LHRH agonists [Zoladex (Z) and Buserelin (B)] have been studied on the proliferation of the human prostatic cancer cell line LNCaP (lymph node carcinoma of the prostate). LNCaP cells were treated for 9 days with different doses of either Z or B (concentrations from 10(-12)-10(-6) M). Both analogs significantly inhibited cell proliferation at doses between 10(-9)-10(-6) M. The antiproliferative action of the two LHRH agonists was shown to be dose dependent, with IC50 values of 0.82 and 1.79 nM for Z and B, respectively. A similar treatment with B was without any significant effect on the proliferation of a mouse embryo fibroblast cell line (Swiss 3T3), which was used as a nontumoral control. The inhibitory action of both LHRH agonists (10(-8) M) on LNCaP cell proliferation was completely antagonized by the simultaneous treatment of the cells with a potent LHRH antagonist (Nal-Arg-LHRH; 10(-8) M); when given alone at the dose selected, the antagonist did not affect cell growth. These results clearly suggest that the antiproliferative effect of LHRH agonists on LNCaP cells may be mediated by specific receptors. The presence of binding sites for [125I]B was consequently demonstrated on the membranes of LNCaP cells cultured in a medium containing charcoal-stripped fetal calf serum, i.e. in the absence of steroids. The affinity of these binding sites for the ligand was lower than that observed for the same receptors on rat pituitary membranes. To clarify the mechanism of the antiproliferative action of the LHRH agonists, the effects of both Z and B on the incorporation of [3H]thymidine and [14C]methionine into LNCaP cells were investigated. During a short incubation period (3 h), the two LHRH agonists rapidly inhibited [3H]thymidine incorporation into the cells. The same treatment did not affect the incorporation of [14C]methionine into proteins.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Antiproliferative effects of luteinizing hormone-releasing hormone agonists on the human prostatic cancer cell line LNCaP. 132 49

The long-term effect of the luteinizing hormone-releasing hormone analogue-induced initial testosterone surge in the treatment of patients with metastatic carcinoma of the prostate still is unknown. However, acute worsening of the disease has been reported in up to 10% of the patients. To prevent such tumor flare we investigated the endocrinological effects of different types of antiandrogens administered in addition to a luteinizing hormone-releasing hormone analogue. Patients with newly diagnosed metastatic prostate cancer were pre-treated with either the steroidal antiandrogen cyproterone acetate (6) or the nonsteroidal antiandrogen flutamide (5) for 1 week before the initial injection of the depot luteinizing hormone-releasing hormone analogue Zoladex. In another 5 patients flutamide was first given 24 hours before Zoladex therapy was started. Luteinizing hormone, testosterone and prostatic acid phosphatase during month 1 of luteinizing hormone-releasing hormone analogue therapy were compared to data obtained in 5 patients treated by Zoladex alone. Only pre-treatment with cyproterone acetate was capable of preventing the Zoladex-induced testosterone surge. However, both pre-treatment regimens with either cyproterone acetate or flutamide for 1 week prevented an initial increase in prostatic acid phosphatase beyond pre-treatment levels in all patients. In contrast, in 4 of 5 patients treated with Zoladex alone and in 2 of 5 pre-treated with flutamide for 1 day an initial increase in prostatic acid phosphatase beyond the pre-treatment values was seen. Our data indicate that pre-treatment with flutamide for only 1 day may not be sufficient to prevent a luteinizing hormone-releasing hormone analogue-induced tumor flare in all cases.
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PMID:Influence of different types of antiandrogens on luteinizing hormone-releasing hormone analogue-induced testosterone surge in patients with metastatic carcinoma of the prostate. 214 96

In patients with locally advanced (bulky) carcinoma of the prostate, definitive radiotherapy is associated with a high rate of local recurrence. The Radiation Therapy Oncology Group (RTOG) has conducted several studies evaluating hormonal cytoreduction (used as an induction regimen) as a means of improving the local control rate. RTOG 85-19 tested an induction regimen consisting of a depot LH-RH agonist (Zoladex) and an antiandrogen (flutamide). Eligible patients were those with bulky primary lesions (stage B2 and C) with disease confined to the pelvis. Zoladex was administered every 29 days via a subcutaneous injection. Flutamide was given by mouth in a dose of 250 mg t.i.d. Administration of the drugs was initiated 2 months prior to start of radiotherapy and was terminated at completion of the radiotherapy course. Radiotherapy consisted of 180-200 rad/day, 4,400-4,500 rad to the regional lymphatics, and 6,500-7,000 rad to the prostate. The primary aim of the study was to evaluate the effectiveness and toxicity of the combined (hormonal cytoreduction plus definitive radiotherapy) regimen. Thirty-one patients were accessioned; 30 are analyzable. The drug-related toxicity appears acceptable. It included appearance of diarrhea before initiation of radiotherapy in two patients, nausea during the 2nd week of drug administration in two patients, and skin rash in three patients. These phenomena appear to be related to flutamide. Hot flashes were recorded in 17 patients. With a minimum follow-up of 2 years, clearance of the primary lesions (by clinical examination) was documented in 28 of 30 patients. During the 1st year, two of 30 patients died (of unrelated causes) with residual palpable tumors. The observed toxicity appears acceptable and the response rate encouraging. A phase III study comparing the tested regimen against radiotherapy alone appears warranted.
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PMID:Phase II Radiation Therapy Oncology Group study of hormonal cytoreduction with flutamide and Zoladex in locally advanced carcinoma of the prostate treated with definitive radiotherapy. 214 72

A new longer-acting depot formulation containing 10.8 mg Zoladex was administered subcutaneously without anesthetic to 35 patients with advanced carcinoma of the prostate. Pharmacodynamic and pharmacokinetic data show that following a transient elevation in serum LH and testosterone, the levels of both hormones decrease. Serum testosterone reaches the castrate range in all patients by week 4 and remains at this level for at least 12 weeks. The serum Zoladex profile shows that castrate serum testosterone values can be sustained by very low serum concentrations of the drug of around 0.05 ng/ml. In this preliminary report, the efficacy and safety of this new longer-acting 3-month depot formulation of 10.8 mg Zoladex has been shown to be comparable to the 1-month depot formulation of 3.6 mg Zoladex, in patients with advanced carcinoma of the prostate.
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PMID:A new longer-acting LHRH analog depot: preliminary results of a Dutch open phase II clinical study on a 10.8 mg Zoladex 3-monthly depot. 215 Dec 71

The study comprised 262 patients with previously untreated advanced carcinoma of the prostate. Patients were randomized either to undergo orchidectomy or to receive combined treatment with Zoladex, 3.6 mg every 4 weeks, plus flutamide, 250 mg t.i.d. At present the median follow-up is 39 months. The objective response to therapy was better in the Zoladex plus flutamide group, but no differences in subjective response, time to disease progression, or survival have been demonstrated between the 2 groups. Adverse effects were more common in the Zoladex plus flutamide group. Thus, 'total androgen blockade' with Zoladex plus flutamide was not clinically superior to orchidectomy in the treatment of patients with advanced prostatic cancer.
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PMID:Zoladex plus flutamide vs. orchidectomy for advanced prostatic cancer. Danish Prostatic Cancer Group (DAPROCA). 215 Dec 75

Various methods have been used clinically to assess prostatic function. We evaluated a number of ways of using zinc in post-prostatic massage urine (VB3) and found that the ratio of VB3 zinc concentration to initial urinary zinc concentration was a good indicator of prostatic secretory activity. This ratio can differentiate hormonally treated patients with carcinoma of the prostate from those untreated and from those with benign prostatic hypertrophy. The specificity is increased for individuals by repeat samples. Comparison of samples before and after resection showed no loss of function and no difference was found between groups treated with orchiectomy or LHRH agonist (Zoladex). The VB3/VB1 zinc concentration could be used in a prospective study of hormonal treatments directed against the prostate, where it could give objective evidence of a fall in secretory function of the gland.
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PMID:Ratio of post-prostatic massage urinary zinc concentration to initial urinary zinc concentration. An improved method of assessing prostatic function. 246 94

The first interim report of this multicentre prospective clinical trial to compare the efficacy of 'Zoladex' versus 'Zoladex' + flutamide in the treatment of advanced carcinoma of the prostate furnishes evidence of a reduction of the incidence of tumour flare within the first 4 weeks of therapy. The combination of 'Zoladex' and flutamide produced an earlier response in tumour markers (TAP, PAP) only. The combination, however, had no effect on subjective and objective response rates and had a negative effect on time to treatment failure. Flutamide produces a significant increase in toxicity and withdrawals due to toxicity. This interim analysis indicates that the continued administration of flutamide in combination with 'Zoladex' has no significant clinical benefit over that of 'Zoladex' alone. Further follow-up is required to determine whether combination treatment has any effect on time to treatment failure and survival.
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PMID:'Zoladex' versus 'Zoladex' plus flutamide in the treatment of advanced prostate cancer. First interim analysis of an international trial. International Prostate Cancer Study Group. 252 37

An LHRH agonist, Zoladex, was employed as a monthly depot in 56 previously untreated patients with advanced carcinoma of the prostate. Of 53 evaluable patients, 27 achieved partial remission and 7 were stable. Median duration of response was 10 months. A favorable subjective response was attained in 68% of the patients. During treatment, serum testosterone was in the castrate range in all patients except five. Possible explanations for this escape phenomenon are discussed. No toxicity was observed and treatment was well tolerated in all patients. Thirty-two patients underwent bilateral orchiectomy following treatment failure of Zoladex. In one patient partial remission according to protocol criteria was recorded. Treatment with LHRH agonists seems safe and may serve as an alternative to conventional hormonal treatment of advanced carcinoma of the prostate.
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PMID:LHRH analogue as a depot preparation (Zoladex) in the treatment of advanced carcinoma of the prostate followed by orchiectomy as a second line therapy--a phase II study. 252 29

The interim results of the randomised, Phase III trial of Zoladex against castration in the management of patients with metastatic carcinoma of the prostate is discussed. Trials commenced in October 1984 and incorporated 359 patients when recruitment ceased in January 1986. The preliminary report concerns the first 240 patients who had a minimum of 3 months follow-up. Entry criteria included patients who had no previous treatment with the exception of first-line localised radiotherapy and those who had distant bone or soft tissue metastases. Fourteen patients were excluded on the basis of protocol violations. The objective assessment of response was based on the British Prostate Group Criteria and was performed monthly for the first 3 months and 3-monthly thereafter. Pre-treatment disease characteristics of patients in both groups were similar at entry and there were no significant differences in the subjective response data of patients between the orchidectomy (n = 106) and the Zoladex group (n = 120). Objective response rates at 12 and 24 weeks of treatment were also identical for both treatment groups. Serum testosterone concentrations were below the 'castrate' level (less than 2 nmol/L) for Zoladex group as well as the orchidectomy group up to 48 weeks. The drug was well-tolerated with minimal side effects, those resulting from testosterone withdrawal were similar in both groups. The report therefore indicates clearly that this partical formulation of LH-RH analogue provides a valuable alternative to the surgical procedure in the treatment of carcinoma of the prostate.
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PMID:Treatment of patients with advanced cancer of the prostate: phase III trial, zoladex against castration; a study of the British Prostate Group. 296 38

Zoladex is a potent decapeptide analogue of luteinising hormone releasing hormone (LHRH). The drug is formulated as a 3.6 mg depot dispersed in a matrix of d,l-lactide-glycolide copolymer, which is totally biodegradable. This formula releases drug continuously for at least 28 days and reliably suppresses serum testosterone into the castrate range. The effect of the depot was studied in 29 patients with locally advanced or metastatic carcinoma of the prostate. Average age at entry was 71 years (range 52-87) and follow-up was from 13.5 to 34.5 months (median 23). Endocrine studies showed that medical castration was maintained in all cases. Three patients experienced bone pain in the first month of treatment and two others had temporary nephrostomies for worsening ureteric obstruction. Subjective improvement was seen in 23/28 cases (82%). There were no complete responses, but partial response was seen in 24/28 (85.7%) using our own criteria, 24/28 (85.7%) using the criteria recommended by the British Prostate Group (BPG) and 15/28 (53.6%) using NPCP criteria. Stable disease was seen in 3/28 patients (10.7%) by our own or BPG criteria, and in 12/28 patients (42.9%) according to NPCP criteria. Progression of disease was measurable in 21 patients (72.4%) whatever criteria were applied; 11/29 (37.9%) have died, giving a median survival of 10 months (range 2.4-26). Following these encouraging results, a multicentre randomised comparative study with stilboestrol 3 mg daily is being undertaken.
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PMID:Phase II study of Zoladex depot in advanced prostatic cancer with special reference to criteria of response and survival. 296 89


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