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)

Prostate cancer is a disease of older men, with more than 80% of cases being diagnosed in men 65 years of age and older. Broader participation in screening and early detection programs has resulted in many diagnoses being made earlier in the course of the disease. However, an estimated 25-30% of cases among older men will be diagnosed as metastatic disease. These will be men initially diagnosed with metastatic disease as well as men previously treated for localized disease that has progressed to metastatic disease. The treatment of metastatic prostate cancer has been straightforward. Objective prognostic factors are assessed, and recommendations for the most suitable hormonal therapy are made. Androgen withdrawal, androgen blockade, or combination therapy are current first-line treatment modalities. Patients with good prognostic factors will generally do well for a long time, even experiencing a time-limited remission. Patients with a poor prognosis will die of their disease, with median survival being 18 months. Pretreatment assessment of men diagnosed with metastatic prostate cancer should include prognostic factors (tumor volume, histologic grade, DNA ploidy, and prostate specific antigen), health status (comorbidity and performance status), quality of life factors (as a baseline against which to evaluate subjective response and to predict subjective progression), and psychosocial dimensions (sexuality and sexual function, self image, sociability, and social support). Each of these assessment areas will provide important predictors for suitable treatment, response and progression, and survival. The challenge presented is the time and difficulty involved in weighing all these areas and in making an informed physician-patient decision on the most appropriate treatment plan. The physician must direct a health care team to treat metastatic prostate cancer effectively. This team includes oncology nurses, dietitians, social workers, spouses, significant others, and the patient himself.
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PMID:Pretreatment of metastatic disease. Prostate cancer in the older male. 808 88

Androgen ablation by bilateral orchiectomy or by the administration of gonadotropin-releasing hormone (GnRH) agonists has become standard treatment for advanced prostate cancer. However, serum levels of dihydrotestosterone (DHT) remain at about 40% of the precastration levels due to the conversion of the adrenal androgens. Maximal androgen blockade (MAB) aims to block the stimulatory action of this adrenal-derived DHT by adding antiandrogens to surgical or medical castration. Some of the largest and best controlled randomized trials in Europe and the United States have shown statistically better progression-free survival, overall survival, and survival from death by prostate cancer with MAB than with monotherapy with a GnRH agonist or with bilateral orchiectomy. Trial 30853 of the European Organization for Research and Treatment of Cancer (EORTC) compared MAB using a combination of goserelin subcutaneous depot (Zoladex; Zeneca Pharmaceuticals, Macclesfield, UK) and flutamide with bilateral orchiectomy. Some other published trials did not find the differences revealed by EORTC 30853, however, and so an overview or meta-analysis of trials on the effects of MAB was organized jointly by the American Cancer Society, the Urological Group of the EORTC, and the International Prostate Health Council. Preliminary results on some of the 23 trials included in the meta-analysis showed an advantage of the GnRH agonist therapy in combination with an anti-androgen, particularly in time to progression. If time to progression is viewed as improved quality of life due to the absence of symptoms, a net result in favor of the combination therapy is noted. The MAB trials, using flutamide as the antiandrogen, also showed a small but distinct improvement in survival with the combination treatment. An emphasis on prognostic factors allows treatment decisions to be reached more easily.
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PMID:Role of maximal androgen blockade in advanced prostate cancer. 817 10

Androgen deprivation displays the mean therapy of advanced stage prostatic cancer, independently of palliative radiotherapy. The evolution to hormone-resistance status leads to a fatal tumor progression. High-dose fosfestrol (diethylstilbestrol diphosphate) has been suggested to circumvent hormone-resistance and to induce a direct cytotoxic effect. Sixteen patients with hormone-resistant prostate cancer were treated by continuous infusion of high-dose fosfestrol according to two schedules: 10 patients were included in a phase I trial of a daily escalating dose from 1.5 g/d to 4.5 g/d for 7 to 10 days. Six other patients were uniformly treated by 4 g/d for 3.5 h for 5 days. Between each course, patients received orally 300 mg/d fosfestrol and 200 mg/d salicylic acid. The mean age was 65 years (range 51-75). Mean number of courses was two (extremes 1-7). Toxicities: reversible weight gain was observed in five patients. One patient presented a pulmonary edema which was resolved immediately after diuretics. One patient and 9 patients respectively experienced grade III and II (OMS) nausea and vomiting. Transient perineal pruritus occurred in 5 patients. Responses: 15 patients were evaluable (one early death occurred on day 3 from tumor progression complicated by an intravascular coagulation disease). There were four objective stabilizations (NPCP criteria) lasting 2 m, 2 m, 5 m and 10 m respectively. Subjective improvement of pain was observed in five other patients. There was more than 50% reduction of PSA in eight patients. High-dose fosfestrol seems to have some objective activity with moderate toxicity and warrants further investigation.
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PMID:[High dose fosfestrol in phase I-II trial for the treatment of hormone-resistant prostatic adenocarcinoma]. 817 77

Androgen ablation by bilateral orchidectomy has long been considered the gold standard against which other forms of treatment for the management of advanced prostate cancer can be evaluated. It now is recognized that the use of luteinizing hormone-releasing hormone analogs provides a form of primary endocrine therapy that is as effective as surgical castration for the treatment of disseminated disease.
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PMID:Is there a best castration? 825 95

Although treatment of intact adult male rats with the pure antiandrogen flutamide or a luteinizing hormone-releasing hormone (LHRH) agonist alone leads to partial inhibition of ventral prostate weight, maximal inhibition is achieved by combination of the two drugs. Potentializing effects of the two compounds were observed even on prostatic ornithine decarboxylase activity. Because LHRH agonists are widely used to achieve medical castration in men treated for prostate cancer, it is of interest to observe that in the dog, known for being the best model for studies of the action of LHRH agonists, flutamide does not interfere with the potent desensitizing action of the LHRH agonist on pituitary LH secretion, thus supporting the combined use of flutamide with an LHRH agonist for maximal androgen blockade without loss of efficiency of the LHRH agonist. Because prostate cancer is known to show a high degree of heterogeneity of its sensitivity to androgens, we analyzed the effect of combined antiandrogen therapy on parameters more sensitive to androgens than ventral prostatic weight itself. In agreement with its pure antiandrogenic characteristics, flutamide alone has no stimulatory effect on the intraprostatic level of mRNA encoding the C1 or C3 component of prostatic binding protein (PBP), whereas cyproterone acetate (CPA), megestrol acetate (MEG), and, especially, medroxyprogesterone acetate (MPA) markedly stimulate PBP-C1 and PBP-C3 mRNA levels, an effect reversed by flutamide, thus further supporting the intrinsic androgenic activity of all these steroidal derivatives. Similar androgenic effects of the steroidal derivatives were observed on prostatic ornithine decarboxylase activity. Androgen-sensitive Shionogi tumor cells were then used to assess the antiandrogenic/androgenic properties of flutamide and the above-indicated steroidal derivatives. MPA, MEG, CPA as well as spironolactone-stimulated cell proliferation under both in vivo and in vitro conditions, thus illustrating the intrinsic androgenic activity of all these compounds. Flutamide was inactive by itself and reversed the stimulatory effect of all other compounds, thus indicating its pure antiandrogenic activity. Although castration reduces intraprostatic dihydrotestosterone (DHT) to undetectable levels in the rat and guinea pig, the concentration remains at about 50% of the value found in intact men after castration, thus indicating an important contribution of the adrenals to DHT in the human prostate, a finding that requires the addition of an antiandrogen to block the action of this important amount of DHT remaining after castration.
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PMID:Mechanism of action and pure antiandrogenic properties of flutamide. 825 97

Androgen deprivation with triptorelin treatment prior to total prostatectomy gave the opportunity of studying consequent morphological changes in the surgical specimens from 38 men with localized prostatic cancer. Multiple core-needle biopsies were taken prior to treatment and compared to the step-sectioned surgical specimens. The histological changes in the prostate following androgen deprivation include glandular atrophy, nuclear pyknosis, cytoplasmic vacuolation, squamous metaplasia and an increase in the relative amount of stroma. None of these changes could be correlated to pretreatment tumour grade, nor to the volume of the residual tumour. A positive correlation was found between tumour grade prior to therapy and volume of residual tumour after treatment. The treatment was not associated with downgrading of the malignancy. On the contrary, in 16% of the cases, foci of a higher grade were found in the surgical specimens compared to the pretreatment core-needle biopsies.
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PMID:Histopathological changes in androgen-deprived localized prostatic cancer. A study in total prostatectomy specimens. 828 86

Androgen-independent Dunning R3327-AT3 rat prostate tumors are considered an appropriate model of advanced prostate cancer in humans. We recently reported that the progestational steroid melengestrol acetate (MGA) inhibited growth of these tumors on oral administration but also induced a marked involution of adrenals and androgen target organs (prostate, seminal vesicles, and testes). We report herein that the 1-dehydro derivative of melengestrol acetate (dMGA) fed to rats for 21 days also inhibited the growth of Dunning AT3 tumors by approximately 55% without causing a significant regression of adrenals or androgen-dependent tissues. Thus, tumor-growth inhibition was induced by dMGA in the absence of glucocorticoid activity. Cytosolic AT3 tumor fractions obtained by diethylaminoethyl (DEAE)-Sephacel batch chromatography were assayed for lipid- and Ca(2+)-dependent (PKC) and -independent protein kinase activities. Prostatic cytosols had equivalent activity levels of both types of kinases (approximately 2 nmol gamma-[32P]-adenosine 5'-triphosphate (ATP) incorporated mg protein-1 min-1. The PKC activity recovered from the cytosol of untreated AT3 tumors was approximately 4 times higher. Oral administration of dMGA reduced this activity by > 95%. The relationship between protein-kinase activity levels and dMGA-induced growth inhibition of androgen-independent tumors in this animal model is discussed.
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PMID:1-dehydro-melengestrol acetate inhibits the growth and protein kinase C activity of androgen-independent Dunning rat prostatic tumors. 843 75

The role of insulin-like growth factor I (IGF-I) in the growth and development of prostate cancer was studied using established human prostate cancer cell lines. Under steroid and growth factor-free culture conditions, IGF-I significantly stimulated the androgen-independent cell lines PC-3 and DU-145 to incorporate [3H]thymidine into DNA, while the androgen-dependent cell line, LNCaP, was not affected. However, in the presence of dihydrotestosterone (DHT), DNA synthesis of LNCaP cells was stimulated by IGF-I in a dose-dependent manner. None of the cell lines tested secreted an immunoreactive level of IGF-I into their conditioned medium. Characterization of receptors by ligand binding assays revealed that all prostate cancer cell lines tested express specific binding sites for IGF-I with similar dissociation constants (0.23-0.39 nM). Crosslinking studies supported the suggestion that 125I-IGF-I was bound to a receptor on these cells. The IGF-I receptor concentrations of androgen-independent cell lines were significantly higher than those of the androgen-dependent cell line. Androgen appeared to affect neither the expression of IGF-I receptors nor the secretion of IGF-I. The results suggest that IGF-I may play an important role in stimulating the growth and progression of prostate cancer.
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PMID:Insulin-like growth factor I: action and receptor characterization in human prostate cancer cell lines. 848 57

Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF alpha) are two closely related peptides that interact with cell-surface epidermal growth factor receptors (EGFR) to induce receptor tyrosine phosphorylation and activation of intracellular signal-transduction pathways. EGF appears to be the predominant EGF-related growth factor in the normal prostate and in benign prostatic hyperplasia (BPH). Evidence indicates that EGF and TGF alpha are important for maintainence of the structural and functional integrity of the benign prostatic epithelium. The EGF-related peptides are primarily localized to the secretory epithelium of the benign prostate, and their production and secretion is augmented by the presence of circulating androgens. EGFR are located in the basal/neuroendocrine (NE) compartment of the benign prostate and exhibit relatively androgen-independent expression. The EGF-related peptides and EGFR are also present in neoplastic prostatic tissues. There is currently no direct evidence to implicate EGFR activation in the pathogenesis of BPH. However, the EGF-related peptides appear to play a functional role in the growth of prostatic carcinoma cells, with TGF alpha being the predominant growth factor. Numerous investigators have demonstrated the functional significance of a TGF alpha/EGFR-mediated autocrine growth pathway in cultured prostatic carcinoma cells. Studies of cultured prostate cancer cells, but not normal epithelial cells, demonstrate constitutive activation of EGFR. Androgen-independent cancer cells exhibit more EGFR expression and phosphorylation than do androgen-responsive prostate cancer cells. Most studies indicate that EGFR do not play a functional role in androgen-stimulated growth of prostate cancer cells. Several studies have correlated EGFR expression with increased nuclear size and tumor dedifferentiation. Future studies should focus on determining both the prognostic significance of EGFR expression and whether manipulation of EGFR-mediated growth can be exploited for therapeutic benefit in human prostate cancer.
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PMID:Epidermal growth factor-related peptides and the epidermal growth factor receptor in normal and malignant prostate. 858 Oct

Cells possess within their epigenetic repertoire the ability to undergo an active process of cellular suicide termed programmed (or apoptotic) cell death. This programmed cell death process involves an epigenetic reprogramming of the cell that results in an energy-dependent cascade of biochemical and morphologic changes (also termed apoptosis) within the cell, resulting in its death and elimination. Although the final steps (i.e., DNA and cellular fragmentation) are common to cells undergoing programmed cell death, the activation of this death process is initiated either by sufficient injury to the cell induced by various exogenous damaging agents (e.g., radiation, chemicals, viruses) or by changes in the levels of a series of endogenous signals (e.g., hormones and growth/survival factors). Within the prostate, androgens are capable of both stimulating proliferation as well as inhibiting the rate of the glandular epithelial cell death. Androgen withdrawal triggers the programmed cell death pathway in both normal prostate glandular epithelia and androgen-dependent prostate cancer cells. Androgen-independent prostate cancer cells do not initiate the programmed cell death pathway upon androgen ablation; however, they do retain the cellular machinery necessary to activate the programmed cell death cascade when sufficiently damaged by exogenous agents. In the normal prostate epithelium, cell proliferation is balanced by a equal rate of programmed cell death, such that neither involution nor overgrowth normal occurs. In prostatic cancer, however, this balance is lost, such that there is greater proliferation than death producing continuous net growth. Thus, an imbalance in programmed cell death must occur during prostatic cancer progression. The goal of effective therapy for prostatic cancer, therefore, is to correct this imbalance. Unfortunately, this has not been achieved and metastatic prostatic cancer is still a lethal disease for which no curative therapy is currently available. In order to develop such effective therapy, an understanding of the programmed death pathway, and what controls it, is critical. Thus, a review of the present state of knowledge concerning programmed cell death of normal and malignant prostatic cells will be presented.
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PMID:Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer. 860 1


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