Clinical trials point to complexities of chemoprevention for cancer.
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Aspirin↗
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Effect of turosteride, a 5 alpha-reductase inhibitor, on the Dunning R3327 rat prostatic carcinoma.
BACKGROUND: Turosteride (FCE 26073) is a new, potent, and selective 5 alpha-reductase inhibitor. We have investigated its effect on tumor growth, organ weight, and serum hormone levels in rats bearing the androgen sensitive Dunning R3327 prostatic carcinoma. METHODS: Animals with tumor diameters of 0.5-1.5 cm were treated for 9 weeks with turosteride (50 and 200 mg/kg/day, 6 days a week, orally), flutamide (25 mg/kg/day, 6 days a week, orally), and leuprolide (300 micrograms/rat, every 3 weeks, subcutaneously) or they were castrated. RESULTS: Turosteride was ineffective at the dose of 50 mg/kg/day, whereas at 200 mg/kg/ day it significantly decreased tumor growth by 45%. Flutamide and leuprolide were highly effective in reducing tumor growth (70 and 77%), although their effect was slightly lower than that of castration (85%). A significant reduction of ventral prostate weight occurred in rats treated with turosteride at 50 and 200 mg/kg/day (53% and 60%). In contrast to leuprolide and castration, the inhibitory effect of turosteride on tumor growth and prostate weight was not associated to any decrease in serum testosterone. CONCLUSIONS: Turosteride has antitumor activity on Dunning prostatic tumor growth and its role in prostatic cancer treatment is worthy of further investigation.
5-alpha Reductase Inhibitors↗
Effect of early treatment of prostate cancer with the 5alpha-reductase inhibitor turosteride in Dunning R3327 prostatic carcinoma in rats.
BACKGROUND: Turosteride, a selective 5alpha-reductase inhibitor, was reported to be effective in inhibiting the growth of established tumors in the Dunning R3327 rat prostatic carcinoma model. We evaluated the preventive effect of turosteride when administered during the latency period in this prostatic tumor model. METHODS: Turosteride was given orally, 6 days a week for 10-15 weeks, starting at different times: 1) 5 weeks after tumor implantation, when tumors were not yet palpable, or 2) 1 day after tumor implantation. In each experiment, one group of animals was castrated on the first treatment day. RESULTS: When treatment started 5 weeks after tumor implantation, neither turosteride (at 50 and 200 mg/kg/day) nor castration reduced tumor incidence (91-100%). Tumor growth was reduced in groups treated with the highest dose of turosteride and in castrated rats. When treatment started 1 day after tumor implantation, castration resulted in a 62% tumor incidence compared to 100% in controls, while turosteride at 200 mg/kg/day was not effective in reducing tumor incidence. However, as in the previous experiment, the compound was highly effective in reducing tumor growth. CONCLUSIONS: The antitumor activity profile of turosteride seems not to be related to the timing of treatment. Given either 5 weeks or 1 day after tumor implantation, the compound did not reduce tumor take, while it maintained effective tumor growth-inhibiting activity in both cases.
5-alpha Reductase Inhibitors↗
Factors influencing the ratio of free to total prostate-specific antigen in serum.
The ratio of free prostate-specific antigen (f-PSA) to total PSA (t-PSA) in serum, calculated as percent free PSA (f-PSA%), is lower in patients with prostate carcinoma (PCa) than in patients with benign prostate hyperplasia (BPH). This parameter facilitates discrimination between the 2 groups of patients, but there is an overlapping of data. A better understanding of factors influencing this ratio is of practical importance. Therefore, f-PSA% was measured in controls and patients suffering from BPH, PCa and chronic prostatic inflammation with t-PSA concentrations up to 20 microg/l using the IMMULITE assays. The relationships of f-PSA% to clinical situation, age, prostate volume, kind of treatment, and stage and grade of tumor were calculated. Compared with controls or BPH patients, mean f-PSA% values were reduced in PCa patients and in patients with chronic prostatic inflammation. The prostate volume was the most important factor to influence f-PSA%. The difference of f-PSA% between PCa and BPH patients with prostate volumes smaller than 40 cm3 was lost if the prostate volumes exceeded 40 cm3. No relationship of f-PSA% to pTNM stage or grade of tumor was observed. In contrast to t-PSA concentrations, the f-PSA% values were not age-dependent and were not influenced by any kind of treatment in BPH and PCa patients either, which simplifies the use of f-PSA% compared with t-PSA. Thus, for using f-PSA% in clinical practice and for interpreting the data correctly, the advantages shown have to be considered along with the potential limitations of f-PSA%.
Adult↗
Multi-centre trial analysis revisited.
Analyses of multi-centre trials must consider the effects of the individual centres and the possibility of non-constancy of treatment effect differences among centres. This usually means an ANOVA with terms for centres, treatments, and centre x treatment interactions in practice, at least in the U.S.A. Empirical and conventional Bayes methods provide attractive alternatives to conventional ANOVAs for analysing and reporting the findings from multi-centre trials and do not require more restrictive assumptions than the ANOVA approach. These approaches require regarding the centre effects as random instead of fixed, a view which often will reasonably describe outcomes of clinical trials in spite of the fact that the individual centres certainly do not comprise a random sample of all possible centres. The components of these approaches are well understood and have been employed in related applications such as meta-analysis. Combining them in a way that makes their application to routine multi-centre trial analysis relatively straightforward does not appear to have been described previously, and is what forms the topic of this paper. The empirical Bayes approach leads to useful graphical displays, including one with the data superimposed on probability contours of the joint distribution of the individual centre means and standard deviations, which provides a handy way to identify possible outliers. Covariates can be incorporated without difficulty. The Bayes approach, implemented with Gibbs sampling, provides a convenient way to construct posterior and predictive distributions for a variety of useful statistics. We compare the result of empirical and conventional Bayes analyses with the result of fixed and mixed model ANOVAs applied to data from a multi-centre trial.
5-alpha Reductase Inhibitors↗
Planning and analysis of repeated measures at key time-points in clinical trials sponsored by pharmaceutical companies.
In this paper we explore the possible reasons why medical papers reporting clinical trials sponsored by the pharmaceutical industry often analyse repeated measures data at certain key time-points instead of employing sophisticated models of repeated measures proposed by many statisticians. A survey indicated that the priority reason in the industry for having repeated measures in clinical trials is to monitor the trial and to utilize the early results for strategic decision making. We discuss what the common statistical methods do and do not offer for analysis of repeated measures in such clinical trials. We advocate the need to improve the understanding of the medical interest in conducting longitudinal trials in the industry, and to plan and analyse the repeated measures accordingly. We address the medical interest by formulating the problem and give illustrative examples for both phases II and III trials.
Alendronate↗
Measures of Proscar, Hytrin, and Cardura side effects.
The importance of reporting correlations among side effects is examined using studies of BPH drugs as examples. The special relation of placebo effects in studying side-effects of drugs, as opposed to their efficacies, is introduced, and the need for special new controls is presented.
Adrenergic alpha-Antagonists↗
[Drug treatment of androgenetic alopecia in men].
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Adult↗
Exploitable mechanisms for the blockade of androgenic action.
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Androgen Antagonists↗
Synthesis and biological evaluation of 4-(4-(alkyl- and phenylaminocarbonyl)benzoyl)benzoic acid derivatives as non-steroidal inhibitors of steroid 5 alpha-reductase isozymes 1 and 2.
The synthesis and biological evaluation of 4-(4-(alkyl- and phenylaminocarbonyl)benzoyl)benzoic acids (4a-4d) as non-steroidal inhibitors of steroid 5 alpha-reductase are described. The compounds were tested in vitro for inhibitory activity toward rat and human 5 alpha-reductase isozymes 1 and 2 at a concentration of 10 microM. The most active inhibitor for the human type 2 isozyme was 4-(4-(phenylaminocarbonyl)benzoyl)benzoic acid, compound 4c (IC50 = 0.82 microM).
5-alpha Reductase Inhibitors↗
Seizure exacerbation associated with inhibition of progesterone metabolism.
The reduced progesterone metabolite tetrahydroprogesterone is a potent positive modulator of GABA(A) chloride conductance that exerts powerful neuroinhibitiory and anti-seizure effects in animal models. Cyclic natural progesterone use may lessen seizure frequency in women with catamenial seizure exacerbation. We report a case in which efficacy was eliminated during concomitant treatment with a reductase inhibitor. The observation suggests that a reduced metabolite, rather than progesterone itself, was responsible for improved seizure control.
Adult↗
Estimated impact of the prostate cancer prevention trial on population mortality.
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Age Distribution↗
Androgen-deprivation therapy as primary treatment for localized prostate cancer: data from Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE).
BACKGROUND: Prostate cancer is largely an androgen-sensitive disease. Androgen-deprivation therapy (ADT) generally has been used for patients with advanced disease. However, ADT is used increasingly as monotherapy for patients with clinically localized disease. The objective of the current report was to describe the characteristics of patients who underwent ADT for the management of localized disease. METHODS: Cancer of the Prostate Strategic Urologic Endeavor (CaPSURE), which is a national disease registry of men with prostate cancer, was screened to identify patients who received treatment with primary ADT (PADT) between 1989 and 2002 for clinically localized disease (T1-T3,Nx/N0,Mx/M0). Clinical data (including Gleason score, prostate-specific antigen [PSA] level, and T classification) and sociodemographic data (including age, race, education, income, and insurance coverage) were analyzed with chi-square statistical tests. Time to failure data were analyzed using log-rank tests, the Kaplan-Meier method, and Cox proportional hazards regression analyses. RESULTS: Of 7045 men, 993 patients (14.1%) with clinically localized disease received primary ADT. Compared with patients who underwent standard treatment, patients who received PADT had higher risk disease (as defined by PSA level, T classification, and Gleason score) and had more comorbidities. Patients who underwent PADT were older, less educated, had lower income, and were more likely to have Medicare than private insurance. The dominant forms of hormone therapy were luteinizing hormone-releasing hormone (LHRH) monotherapy (48.6%) and combined androgen blockade (LHRH agonist and antiandrogens; 38.8%). At 5 years after the initiation of PADT, 67.3% of patients still were receiving treatment with only androgen deprivation, 103 patients (13.8%) had gone on to receive definitive second treatment (radical prostatectomy, external beam radiotherapy, brachytherapy, or cryotherapy), 27 patients (3.9%) underwent second-line therapy (chemotherapy or alternative hormone-deprivation therapy), 22 patients (4.1%) died of prostate cancer, and 146 patients (19%) died of all causes. CONCLUSIONS: The use of PADT therapy appeared to control disease in the majority of patients who received it, at least for an intermediate period. However, such patients appeared to be unique based on sociodemographic characteristics, comorbidity status, and risk factors compared with patients who received other forms of therapy. The impact of PADT on quality of life needs to be compared with standard therapy, and its long-term durability should be assessed better in patients with prostate cancer.
Adenocarcinoma↗
Serenoa repens (Permixon) inhibits the 5alpha-reductase activity of human prostate cancer cell lines without interfering with PSA expression.
The phytotherapeutic agent Serenoa repens is an effective dual inhibitor of 5alpha-reductase isoenzyme activity in the prostate. Unlike other 5alpha-reductase inhibitors, Serenoa repens induces its effects without interfering with the cellular capacity to secrete PSA. Here, we focussed on the possible pathways that might differentiate the action of Permixon from that of synthetic 5alpha-reductase inhibitors. We demonstrate that Serenoa repens, unlike other 5alpha-reductase inhibitors, does not inhibit binding between activated AR and the steroid receptor-binding consensus in the promoter region of the PSA gene. This was shown by a combination of techniques: assessment of the effect of Permixon on androgen action in the LNCaP prostate cancer cell line revealed no suppression of AR and maintenance of PSA protein expression at control levels. This was consistent with reporter gene experiments showing that Permixon failed to interfere with AR-mediated transcriptional activation of PSA and that both testosterone and DHT were equally effective at maintaining this activity. Our results demonstrate that despite Serenoa repens effective inhibition of 5alpha-reductase activity in the prostate, it did not suppress PSA secretion. Therefore, we confirm the therapeutic advantage of Serenoa repens over other 5alpha-reductase inhibitors as treatment with the phytotherapeutic agent will permit the continuous use of PSA measurements as a useful biomarker for prostate cancer screening and for evaluating tumour progression.
5-alpha Reductase Inhibitors↗
Effect of MK-906, a specific 5 alpha-reductase inhibitor, on serum androgens and androgen conjugates in normal men.
To determine the hormonal effects of MK-906, an orally active 5 alpha-reductase inhibitor, on serum androgens and androgen conjugates, 12 healthy men were given 10, 20, 50, and 100 mg MK-906 2 weeks apart in randomized order in a 4-period crossover design. Serum testosterone (T), dihydrotestosterone (DHT), androstanediol glucuronide, and androsterone glucuronide were measured before and 24 hours after each dose. The effect of MK-906 on glucuronyl transferase activity, the enzyme responsible for androstanediol glucuronide and androsterone glucuronide formation, was assessed in vitro using rat prostate tissue. Serum T levels were unchanged after all doses. Serum DHT, androstanediol glucuronide, and androsterone glucuronide were suppressed by 70, 40, and 56%, respectively, after the 10-mg dose, and by 82, 52, and 66% after the 100-mg dose (P less than 0.02 for the comparison between the 10 and 100-mg doses for all three steroids), respectively. Baseline serum T and DHT levels were strongly correlated (R = 0.89, P = 0.0002), as were androstanediol glucuronide and androsterone glucuronide levels (R = 0.78, P = 0.003), but there was no correlation between DHT levels and the levels of either conjugated steroid. MK-906 had no effect on glucuronyl transferase activity in vitro. It was concluded that single doses of MK-906 suppress both conjugated and unconjugated 5 alpha-reduced androgens. While all three steroids appeared to be good markers of systemic 5 alpha-reductase inhibition, further research will be needed to determine which steroid best reflects tissue DHT levels in patients receiving these inhibitors.
5-alpha Reductase Inhibitors↗
Chemoprevention strategies for prostate cancer: the role of 5 alpha-reductase inhibitors.
Prostate cancer is a major health problem for the aging male population. Despite hormonal dependence, the inevitable emergence of androgen insensitive tumors, which have a dismal prognosis, highlights the need to develop prevention strategies such as chemoprevention. An acceptable agent must interfere with either the process of carcinogenesis or tumor growth, and have minimal toxicity. In clinical studies, 5 alpha-reductase inhibitors have been shown to suppress serum and intraprostatic levels of dihydrotestosterone, an important promoter of prostate cancer, leading to reduction in prostate size and suppression of glandular cell activity as measured by prostate specific antigen secretion. In addition, 5 alpha-reductase inhibitors have demonstrated an excellent safety profile and tolerability in 12 month controlled clinical trials. No significant metabolic effects have been observed in gonadotropin secretion, spermatogenesis, serum lipids or glucose tolerance. The efficacy and safety of 5 alpha-reductase inhibitors in studies to date, combined with the androgen dependence of tumor production, strongly supports investigating their use for chemoprevention of prostate cancer.
5-alpha Reductase Inhibitors↗
Chemoprevention of prostate cancer: guidelines for possible intervention strategies.
The "natural history" of prostate cancer may bedevil the development of guidelines for chemoprevention interventions. Can strategies be designed to direct agents to those lesions which have the potential to develop localized extension that may become symptomatic or metastatic disease? Of necessity our interventions will focus on the identification and quantification of appropriate biomarkers as intermediate endpoints, although no reliable endpoints for prostate cancer have yet been identified. The reduction of prostate cancer incidence may be the ultimate objective, but a decrease in the progression of microfocal or "latent" cancer may well be just as effective as prevention when the age of the target population and competing causes of death are taken into account. Early intervention strategies must focus on the analysis of the interactions of the chosen chemopreventive agents upon precancerous and cancerous cellular dynamics in the prostate. Whether the requirements of such molecular epidemiology necessitate a more deliberate strategy of Phase II studies or a high risk-high gain strategy of a broad Phase III study is open to debate. Factorial designs for proposed randomized chemoprevention trials may be desirable to test multiple chemopreventive agents simultaneously, provided knowledge of the biochemical synergism of the agents is solid. Stratification of study participants by degree of risk will ameliorate concerns regarding the precision targeting of lesions at different stages in the precancer/cancer continuum.
Androstenes↗
Drug or symptom-induced depression in men treated with alpha 1-blockers for benign prostatic hyperplasia? A nested case-control study.
PURPOSE: Regulatory authorities have raised concern that alpha 1-blockers, prescribed predominantly for benign prostatic hyperplasia (BPH), may be associated with an increased risk of depression. The aim was to assess the risk of depression with alpha 1-blockers independently of that associated with symptoms being treated and concurrent illness. METHODS: Using a study population registered on the UK General Practice Research Database, and taking a prescription for an antidepressant as a proxy for clinical depression, we performed: (a) cohort analyses comparing the incidence of depression in current users of alpha 1-blockers versus non-users, and in men with BPH versus those without. (b) A nested case-control analysis looking at the association between depression and alpha 1-blocker exposure, accounting for the presence of BPH and other illness. RESULTS: In the cohort analyses, risk of depression was significantly higher in men with BPH compared to those without (IRR 2.17, 2.12-2.22), but was not significantly different for men exposed to alpha 1-blockers versus those unexposed when adjusted for the presence of BPH. Cases of depression were more likely to have pre-existing BPH (crude OR 2.09, 2.02-2.15) than controls. After adjusting for concurrent illness (using number of GP visits as a proxy) and the presence of BPH (adjusted OR 1.38, 1.33-1.43), there was no association with depression for exposure to any alpha 1-blocker (adjusted OR 1.03, 0.90-1.18). CONCLUSIONS: This study did not suggest that the prescribing of alpha 1-blockers increases the risk of being depressed. The association highlighted by spontaneous reporting systems appears to be explained by confounding by concurrent disease.
Adrenergic alpha-1 Receptor Antagonists↗