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At least 1,315 records · Page 73Linked to original sources
PubMed2004

Combined modality treatment in the management of high-risk prostate cancer.

PURPOSE: The efficacy of a multimodality protocol using neoadjuvant and concomitant hormonal therapy, brachytherapy, and three-dimensional conformal external beam radiotherapy (RT) in high-risk prostate cancer was evaluated using biochemical outcomes and posttreatment biopsy results. METHODS AND MATERIALS: Between February 1994 and November 1999, 132 high-risk patients were treated with combined hormonal therapy (9 months), permanent radioactive seed brachytherapy, and external beam RT, with follow-up ranging from 36 to 88 months (median, 50 months). The eligibility criteria were any of the following: Gleason score 8-10, initial prostate-specific antigen (PSA) level >20 ng/mL, clinical Stage T2c-T3, or positive seminal vesicle biopsy, or two or more of the following: Gleason score 7, PSA level >10-20 ng/mL, or Stage T2b. Twenty percent of patients had a positive seminal vesicle biopsy before therapy. Negative laparoscopic pelvic lymph node dissections were performed in 44% of patients. RESULTS: The actuarial overall freedom from PSA failure rate was 86% at 5 years. The freedom from PSA failure rate at 5 years was 97% for those with a Gleason score of < or =6 (35 of 36), 85% for a Gleason score of 7 (50 of 59), and 76% for a Gleason score of 8-10 (28 of 37; p = 0.03). A trend was noted toward worse outcomes in seminal vesicle biopsy-positive patients, with a 5-year freedom from PSA failure rate of 74% vs. 89% for all other patients (p = 0.06). Posttreatment prostate biopsies were performed in 47 patients and were negative in 96% at the first biopsy and 100% at the last biopsy. CONCLUSION: Trimodality therapy with androgen suppression, brachytherapy, and external beam RT for high-risk prostate cancer results in excellent biochemical and pathologically confirmed local control.

Androgen Antagonists↗
PubMed2003

Hormonal therapy options for patients with a rising prostate-specific antigen level after primary treatment for prostate cancer.

At this time, many treatment options exist for primary androgen-deprivation therapy. "Standard" options with long-term results on outcome include orchiectomy, monotherapy with a luteinizing hormone-releasing hormone (LHRH) agonist, and combined androgen blockade using an LHRH agonist and antiandrogen. All treatments are associated with some morbidity related to the reduction of circulating testosterone. For this reason, "alternative" regimens are under active study to determine whether equal outcomes can be achieved with lesser toxicity.

Adenocarcinoma↗
PubMed2005

Approach to management of clinically localized prostate cancer in patients with human immunodeficiency virus.

OBJECTIVES: To evaluate the approach to management of localized prostate cancer (PCa) in patients with human immunodeficiency virus (HIV) in the highly active antiretroviral therapy era. METHODS: A retrospective analysis was performed on 10 HIV-positive patients who recently presented with elevated prostate-specific antigen levels and clinically localized PCa. RESULTS: At the diagnosis of PCa, the average patient was 54.0 years old, had been HIV positive for 8.75 years, had a CD4 count of 417, a prostate-specific antigen level of 9.2 ng/mL, and a Gleason score of 6. Eight of the patients had risk factors for PCa--either African-American descent (n = 6) or a positive family history (n = 2). The treatment was laparoscopic radical prostatectomy in 1, potency-preserving androgen deprivation in 1, cryosurgery in 1, brachytherapy in 2, observation in 2, and external beam radiotherapy in 3. CONCLUSIONS: Screening of all HIV-positive men should be initiated at age 40 if they have either a positive family history of prostate cancer or are of African-American descent. Asymptomatic HIV-positive patients should be offered all therapeutic PCa treatment options.

Adenocarcinoma↗
PubMed1997

A putative 5 alpha-reductase inhibitor demasculinizes portions of the zebra finch song system.

One model of the sexual differentiation of the zebra finch song system holds that both major metabolites of testosterone, dihydrotestosterone (DHT) and estradiol (E2), act together to masculinize the song system. To test this model, we administered a putative inhibitor of 5 alpha-reductase (MK-434) to decrease the synthesis of DHT from testosterone (T) in hatchling zebra finches. We tested MK-434's inhibition of 5 alpha-reductase, 5 beta-reductase, and aromatase in vivo and in vitro. In vivo, MK-434 significantly inhibited 5 alpha-reductase activity but also reduced the activities of 5 beta-reductase and aromatase. In vitro, MK-434 was extremely effective in inhibiting 5 alpha-reductase in the rat prostate but only slightly inhibited 5 alpha-reductase in the zebra finch telencephalon, where it also reduced aromatase and 5 beta-reductase activities. These results suggest that MK-434 might differentially influence the availability of androgenic and estrogenic substrates, depending on the relative abundance of these enzymes in brain. MK-434 demasculinized (decreased) the number and decreased the density of RA neurons but did not significantly affect any other sexually dimorphic aspect of the song system, including the volumes of RA, HVC, and Area X; the size of neural somata in IMAN, HVC, and RA; and the number of neurons in HVC and IMAN. The differential influence of MK-434 on sexually dimorphic characteristics suggests that the various sexually dimorphic characteristics of the song system (1) are sensitive to different hormones, depending on the characteristic; or (2) have different sensitivities to hormone levels, some being easily affected by slightly reduced hormone levels whereas others are not; or (3) have markedly different critical periods depending on the characteristic. Regardless of the reason(s) for differential effects on the sexually dimorphic characteristics of the song system, the data clearly suggest that steroid hormones play a role in the normal masculine development of the song system.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1997

Regulation of proopiomelanocortin gene expression by endogenous ligands of the GABAA receptor complex as evaluated by in situ hybridization in the rat pars intermedia.

The neurotransmitter gamma-aminobutyric acid (GABA) exerts a tonic inhibitory influence on proopiomelanocortin (POMC) neurons in the hypothalamus as well as on the melanotrope cells of the intermediate lobe (IL) of the pituitary gland. Moreover, the activation of the GABAA receptor complex by different ligands has been shown to exert a negative influence on the POMC gene expression at the hypothalamic level. In order to elucidate the in vivo regulation of the POMC mRNA levels in the intermediate lobe of the pituitary by endogenous ligands of the GABAA receptor complex, we have studied the effect of intravenous (i.v.) and intracerebroventricular (i.c.v) injections of octadecaneuropeptide (ODN), a peptide derived from diazepam-binding inhibitor (DBI). The possible involvement of neurosteroids in the action of ODN on melanotropic cells was evaluated following inhibition of two enzymes involved in the biosynthesis of neurosteroids known as activators of G3BAA receptor complex: trilostane, an inhibitor of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), and MK-906, an inhibitor of 5 alpha-reductase. The i.v. injection of ODN produced a dose-dependent inhibition of POMC gene expression in the IL. The i.c.v. injection of ODN also depressed POMC mRNA. These effects were completely reversed by the concomitant administration of the GABAA antagonist picrotoxin. Similar results were obtained in POMC neurons in the arcuate nucleus (AN) of the hypothalamus. Trilostane administration induced an increase in POMC mRNA and also prevented the inhibitory influence of ODN. The neurosteroid pregnenolone-sulfate, a negative modulator of the GABAA receptor, also stimulated POMC gene expression. On the other hand, MK-906 produced a decrease in mRNA levels and could not reverse the effect of ODN. The results indicate that activation of the GABAA receptor complex by the endogenous benzodiazepine receptor ligand ODN can induce a negative regulation of POMC gene expression in the IL of the pituitary and neurons in the AN. The present results do not provide clear evidence that neurosteroids are involved in the action of ODN on POMC gene expression in the IL.

Adrenalectomy↗
PubMed1992

Sequential androgen blockade: a biological study in the inhibition of prostatic growth.

We attempted to determine the effects of the combination of a 5-alpha reductase inhibitor and an antiandrogen on rat ventral prostate and seminal vesicle weight. We also attempted to determine whether the prostatic cell death gene TRPM-2 would be expressed using this combination of drugs. Adult male Sprague-Dawley rats were randomly assigned to 7 groups of 15 animals. Four groups served as controls: an intact group sacrificed at the initiation of the trial (group 1), a castrate control group (group 2), an intact control group (group 3), and a group treated with the combination of an LHRH agonist plus antiandrogen (group 7). Three other groups were treated with daily subcutaneous injections of 5 alpha reductase inhibitor (group 5), a nonsteroidal pure antiandrogen (group 4) or both (group 6). After 5 days of treatment 5 animals in each group were sacrificed and prostatic tissue was assayed for the androgen repressed prostatic cell death gene TRPM-2. At 30 days (35 days for group 7) the remaining animals were sacrificed and their ventral prostates, seminal vesicles, and testes (except group 3) were weighed. The combination group (group 6) had a significantly lower prostate weight than either of the monotherapy groups (4, 5), or intact control groups, was equivalent to group 7 but was significantly heavier than the castrate group 2. The seminal vesicle weights of the combination group 6 were significantly lower than the monotherapy groups (4, 5), intact control group, castrate group (3) and was equivalent to group 7. Only castration was able to induce expression of the cell death gene TRPM-2. In this model, the combination of 5 alpha reductase inhibitor and an antiandrogen is as effective a mode of androgen ablation as combination therapy of LHRH agonist plus antiandrogen. Clinically, this combination may translate into adequate androgen blockade without impotence or other side effects of testosterone deprivation. Clinical trials appear warranted to assess this hypothesis.

5-alpha Reductase Inhibitors↗
PubMed1997

Hypothalamic aromatase cytochrome P450 and 5alpha-reductase enzyme activities in pregnant and female rats.

The metabolism of steroid hormones in the medial basal hypothalamus (MBH) is known to play a critical role in neural development, the modulation of neuroendocrine function and regulating sexual behavior. While the important biological functions of the aromatase enzyme are well established, the importance of brain 5alpha-reductase has been revealed and elucidated only in the last few years. The distribution and regulation of brain aromatase and 5alpha-reductase enzyme activities have been investigated for the most part in male rats. Therefore, in the present study, MBH aromatase cytochrome P450 and 5alpha-reductase activities were characterized in pregnant and female rats during postnatal development under various hormonal conditions. MBH aromatase activity was determined in each tissue sample using the 'tritiated water release' assay, whereas, the 5alpha-reductase rates were determined by thin layer chromatography and scintillation counting of the isolated 5alpha-metabolites. Both activities were highest in infantile animals, then declined with increasing postnatal age; whereas, in aged non-cycling or ovariectomized/adrenalectomized (Ovx/Adx) rats high rates of androgen metabolism were seen in MBH tissue. No significant alterations in MBH aromatase were observed when the 5alpha-reductase pathway was blocked in pregnant animals during late gestation with a known 5alpha-reductase inhibitor (Proscar). However, plasma estradiol levels were significantly increased in the Proscar-treated animals. These results indicate that: 1) the decreasing MBH aromatase and 5alpha-reductase profile (in infantile to adult cycling animals) is developmentally regulated, 2) evidently, there is a divergent regulatory mechanism controlling MBH aromatase versus 5alpha-reductase in aged animals where the aromatase activity increased in aged non-cycling and Ovx/Adx rats while 5alpha-reductase rates remained at moderate levels and, 3) apparently, the 5alpha-reductase pathway is not involved in regulating MBH aromatase activity during late pregnancy.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1993

Medical treatment of benign prostatic hyperplasia: 5 alpha-reductase inhibitors and alpha-adrenergic antagonists.

Benign prostatic hyperplasia (BPH), a nonmalignant neoplasm of the prostatic epithelial and stromal tissue, occurs commonly in elderly men. The "gold standard" of care for symptomatic BPH has been and remains transurethral resection of the prostate. This operation, however, like any surgical procedure, has associated morbidity and imposes an appreciable expense on the health-care system; therefore, enthusiasm for the development of medical therapies for the management of symptomatic BPH has been substantial. Currently, practicing physicians have two types of medications for the treatment of symptomatic BPH: 5 alpha-reductase inhibitors and alpha-adrenergic antagonists. The former drugs inhibit the conversion of testosterone to the potent prostatic androgen dihydrotestosterone. As a result, the androgenic stimulation to the prostate gland is suppressed, and the size of the prostate is decreased by approximately 25%. In some patients, this outcome decreases the mechanical obstruction of the prostatic urethra and improves micturition. alpha-Adrenergic antagonists decrease the smooth muscle tone of the bladder neck, prostatic adenoma, and prostatic capsule. After these structures have been relaxed, resistance to urine flow through the prostatic urethra can be decreased, and obstructive voiding symptoms can be resolved. Although two distinctly different mechanisms are involved, both types of medications are effective for treating BPH. Thus, in 1993, transurethral resection of the prostate is no longer the only available therapeutic option. With the advent of medical therapies, internists and primary-care physicians will have more involvement in the care of patients with BPH than previously. Therefore, urologists and nonurologists must work together to serve the needs of patients with prostatism.

5-alpha Reductase Inhibitors↗
PubMed1998

Androgen metabolism in cultured rat renal inner medullary collecting duct (IMCD) cells.

Although the stimulations of renal hypertrophy and renal erythropoietin production have been well-known androgen effects in the kidney, recent investigative progresses are further providing good evidences for androgen-regulated gene productions of key enzymes or local hormone substrates important to renal cell metabolisms and tubular functions in mouse or rat proximal tubules, respectively. It has been also reported that testosterone restores vasopressin receptors in medullary collecting ducts of the ageing rat and improves a urinary concentrating ability. Therefore in the present study we examined a metabolic pathway of androgens in cultured rat renal IMCD cells, which finally determine a urinary composition and volume. IMCD cells cultured from kidneys of male Wistar rats weighing about 200 g were incubated with serum-free culture media containing 4 nM [3H] testosterone or [3H] androstenedione for 2-48 h. Radioactive compounds in incubation media were then separated by reverse-phase high-pressure liquid chromatography (HPLC) and identified mainly on the basis of comparison of retention times of standard materials on HPLC. The main metabolites identified in testosterone or androstenedione incubation experiment were 5 alpha-dihydrotestosterone or 5 alpha-androstanedione, respectively. 5 alpha-Reductase inhibitor, MK 906, effectively inhibited the formations of these Ring A reduced metabolites. These results may suggest that rat renal IMCD cells possess 5 alpha-reductase activity, thereby converting androgens into their biologically active forms in vivo.

5-alpha Reductase Inhibitors↗
PubMed2001

Prostate cancer prevention agent development: Criteria and pipeline for candidate chemoprevention agents.

Epidemiologic data suggest that prostate cancer morbidity and mortality ought to be preventable. New insights into the molecular pathogenesis of prostate cancer offer new opportunities for the discovery of prostate cancer chemoprevention drugs and new challenges for their development. Established pathways that lead to US Food and Drug Administration (FDA) approval of drugs for advanced prostate cancer may not be appropriate for the development of drugs for prostate cancer chemoprevention. For example, large randomized clinical trials designed to test the efficacy of new chemoprevention drugs on prostate cancer survival in the general population are likely to be conducted at great expense and take many years, threatening to increase commercial development risks while decreasing exclusive marketing revenues. As a consequence, to accelerate progress in research, new validated surrogate and strategic clinical trial endpoints, and new clinical trial designs featuring more precisely defined high-risk clinical trial cohorts, are needed. In this review, 10 criteria for prostate cancer chemoprevention agent development are offered and the pipeline of new prostate cancer chemoprevention drug candidates is considered.

Androgen Antagonists↗
PubMed2001

The Prostate Cancer Prevention Trial: Current status and lessons learned.

The Prostate Cancer Prevention Trial is the first phase 3 prevention trial for prostate cancer in the United States. The implementation of a large, randomized trial has provided a wealth of information that will aid in future cancer chemopreventive studies in US men. The experience from the implementation of the Prostate Cancer Prevention Trial was reviewed. Lessons learned from the study include: (1) US men are willing to enroll in prevention trials; (2) participants in chemoprevention trials are well educated and healthy; (3) the successful cancer prevention trial is viewed by participants as a "men's health trial"; (4) data management and discipline coordination at participating institutions are critical; (5) study design change is commonly required owing to changes in clinical practice over the course of the trial; and (6) training of institutional staff is essential. With proper design, robust data management, and a flexible staff, large-scale randomized chemoprevention trials can be accomplished in the United States. With the extraordinary number of potential agents, it is expected that much will be accomplished with this strategy in the near future.

5-alpha Reductase Inhibitors↗
PubMed2001

Androgen deprivation therapy for patients with clinically localized (stages T1 to T3) prostate cancer and for patients with biochemical recurrence after radical prostatectomy.

Recently published studies suggest a benefit for androgen deprivation therapy (ADT) delivered early in the course of prostate cancer. However, the use of ADT specifically in patients with clinically localized disease or biochemical-disease recurrence after local therapy is not well defined. Potential candidates for primary ADT include patients who are poor candidates for definitive local therapy because of advanced age or comorbid conditions, as well as patients with significant local disease who refuse standard therapy. Treatment strategies designed to minimize the side effects of prolonged therapy, such as intermittent ADT or antiandrogen monotherapy, show promise as alternatives to continuous ADT in some patients. The role of ADT in patients with clinically localized and recurrent prostate cancer, whether it is delivered in a continuous or intermittent fashion, must be determined in randomized, prospective trials.

Androgen Antagonists↗