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)

Serum prostate-specific antigen (PSA) levels were studied in the EORTC trial of zoladex plus flutamide versus orchidectomy in metastatic prostatic cancer. Forty-four of 60 patients had a decrease of PSA to less than or equal to 10 ng/ml at 3 to 6 months after treatment. The combination of a PSA less than 10 ng/ml after 3 to 6 months treatment and less than 15 spots on the bone scintigram at entry gave the highest probability of not having progressed by 24 months. A rising PSA anticipated bone progression by 6 to 12 months in 13 of 28 patients (46%). The PSA at entry to the trial was related to survival; a discriminant of 300 ng/ml distinguished a poor and better risk group. The lowest level of PSA reached during the first 6 months of treatment was also a univariate survival factor.
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PMID:Prostatic specific antigen and the prediction of prognosis in metastatic prostatic cancer. 169 98

The study of prognostic factors in patients with prostate cancer (Pca) may be of value in understanding the natural history of the disease and may also assist in planning and analyzing the results of clinical trials. Moreover some information through this study would be beneficial to assessing the prognosis and decision of better therapy form of individual patients. The significance of items studied was evaluated from the two view points, survival rate and Pca death rate. Stage, pathological differentiation and acid phosphatase were significantly related to them, in the category grade depending manner. Past history and complication, and age were also significantly related to them but higher category grade as a survival factor showed lower Pca death rates. ESR, gait disturbance and hematuria were related to only survival rate. Any significant relationship was not observed in serum testosterone, voiding disturbance and cancer-pain. Prognostic factors should be clinically used through the well understanding of each characteristics. This paper also showed that statistical significance not always provide a wide difference between categories compared.
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PMID:[Prognostic factor for prostate cancer. Gunma Urological Oncology Study Group]. 223 14

Beta-carotene, canthaxanthin and retinoic acid (RA) inhibited growth of human DU145 prostate cancer cells by 45, 56 and 18%, respectively. Lycopene was also found to inhibit cell growth. Other carotenoids including xanthophyll (lutein), cryptoxanthin and zeaxanthin were less effective. Liarozole (a novel imidazole-derived inhibitor of intracellular RA catabolism) had a modest effect upon cell growth, this drug significantly amplified the pro-apoptotic actions of beta-carotene and RA. RA-induced expression of thymosin beta-10, an apoptotic accelerant, was associated with increased nuclear DNA nicking as measured using TUNEL. Liarozole enhanced the proapoptotic actions of RA upon DNA fragmentation in a dose-dependent manner. These actions were accompanied by inhibition of the cell survival factor bcl-2. Liarozole may thus prove useful as a novel chemotherapeutic/chemopreventive agent by boosting retinoid-induced apoptosis in the prostate.
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PMID:Liarozole amplifies retinoid-induced apoptosis in human prostate cancer cells. 879 6

Antioxidant defenses play a critical role in the regulation of programmed cell death, even when death is induced by nonoxidative stimuli. During spermatogenesis, most of the testicular germ cells degenerate by an apoptotic process that is under hormonal control. However, the exact mechanisms by which hormonal signals are transduced within the cells to direct their life, and whether other effectors of the apoptotic pathway, for example antioxidants, take part in the control of human germ cell survival, are not known. In the present study, testosterone and N-acetyl-L-cysteine (NAC), which is an antioxidant, an inhibitor of apoptosis in several systems, and a survival factor in human semen, were found to suppress programmed cell death in human testicular germ cells in vitro. The samples came from adult men undergoing orchidectomy for prostate cancer. Germ cell death was induced by incubating segments of seminiferous tubules under serum-free culture conditions. This apoptosis, detected by Southern blot analysis of DNA fragmentation, by DNA labeling in situ, and by morphological analysis under the electron microscope, was significantly inhibited by testosterone at concentrations of 10(-6) and 10(-7) mol/L. NAC concentrations of 125, 100, 50, and 25 mmol/L suppressed germ cell death in a dose-dependent manner. This inhibition was effective during 4, 24, and 48 h of incubation. Apoptotic cells were identified mainly as spermatocytes and early spermatids. Programmed cell death was also demonstrated in late spermatids. We conclude that NAC, which is an antioxidant, plays an important role in germ cell survival in the human seminiferous tubules in vitro. We also suggest NAC as a possible new therapeutic factor for some men with idiopathic oligospermia.
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PMID:N-acetyl-L-cysteine inhibits apoptosis in human male germ cells in vitro. 966 38

Diets high in fat are associated with an increased risk of prostate cancer, although the molecular mechanism is still unknown. We have previously reported that arachidonic acid, an omega-6 fatty acid common in the Western diet, stimulates proliferation of prostate cancer cells through production of the 5-lipoxygenase metabolite, 5-HETE (5-hydroxyeicosatetraenoic acid). We now show that 5-HETE is also a potent survival factor for human prostate cancer cells. These cells constitutively produce 5-HETE in serum-free medium with no added stimulus. Exogenous arachidonate markedly increases the production of 5-HETE. Inhibition of 5-lipoxygenase by MK886 completely blocks 5-HETE production and induces massive apoptosis in both hormone-responsive (LNCaP) and -nonresponsive (PC3) human prostate cancer cells. This cell death is very rapid: cells treated with MK886 showed mitochondrial permeability transition between 30 and 60 min, externalization of phosphatidylserine within 2 hr, and degradation of DNA to nucleosomal subunits beginning within 2-4 hr posttreatment. Cell death was effectively blocked by the thiol antioxidant, N-acetyl-L-cysteine, but not by androgen, a powerful survival factor for prostate cancer cells. Apoptosis was specific for 5-lipoxygenase-programmed cell death was not observed with inhibitors of 12-lipoxygenase, cyclooxygenase, or cytochrome P450 pathways of arachidonic acid metabolism. Exogenous 5-HETE protects these cells from apoptosis induced by 5-lipoxygenase inhibitors, confirming a critical role of 5-lipoxygenase activity in the survival of these cells. These findings provide a possible molecular mechanism by which dietary fat may influence the progression of prostate cancer.
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PMID:Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells. 978 62

Multiple population-based studies show an increased risk of prostate cancer in populations that consume large amounts of animal fat. However, the molecular mechanisms linking dietary fat to prostate cancer biology remain obscure. Animal fats are typically rich sources of arachidonic acid and this fatty acid is converted to a wide range of powerful compounds including leukotrienes, prostaglandins, etc. We have shown that PC3 and LNCaP convert arachidonic acid to the 5-lipoxygenase product, 5-HETE. When the formation of 5-HETE is blocked, human prostate cancer cells enter apoptosis in less than 1 h and are dead within 2 h. Exogenous 5-HETE can rescue these cancer cells. These findings indicate that 5-HETE is a potent survival factor for human prostate cancer cells.
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PMID:Lipoxygenase inhibition in prostate cancer. 1032 95

In this study, the potential interactions between dihydrotestosterone (DHT), a survival factor, and transforming growth factor-beta (TGF-beta), an apoptotic inducer, were examined in a derivative of the hormone-sensitive prostate cancer cell line LNCAP: The LNCaP TGF-beta receptor II cells, engineered to express TGF-beta receptor II, are sensitive to both DHT and TGF-beta. Surprisingly, when the LNCaP TGF-beta receptor II cells were treated with TGF-beta in the presence of physiological levels of DHT, both cell cycle arrest and apoptosis induction were significantly enhanced over TGF-beta alone. This effect temporally correlated with an increased expression of the cell cycle regulator p21 as well as the apoptotic executioner, procaspase-1, and a parallel down-regulation of the antiapoptotic protein, bcl-2. Expression of bax and caspase-3 proteins remained unchanged following treatment. Furthermore, apoptosis induction was suppressed by the caspase-1 inhibitor, z-YVAD, but not the caspase-3 inhibitor, z-DQMD, thus demonstrating the functional significance of increased procaspase-1 expression in TGF-beta-mediated apoptosis in prostate cancer cells. These results indicate that TGF-beta-mediated apoptosis can actually be enhanced by androgens through specific mechanisms involving cell cycle and apoptosis regulators and provide initial evidence on the ability of physiological levels of androgens to stimulate the intrinsic apoptotic potential of prostate cancer cells. Therefore, this study provides a molecular basis for the priming of prostate cancer cells for maximal apoptosis induction, during hormone- ablation therapy.
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PMID:Dihydrotestosterone enhances transforming growth factor-beta-induced apoptosis in hormone-sensitive prostate cancer cells. 1135 90

We review the extensive body of data on the molecular aetiology of hormone refractory disease in metastatic prostate cancer patients. Particular emphasis is placed on the crucial role of the bone micro-environment, especially the intercellular interactions of metastatic prostate cancer cells and osteoblasts in promoting the establishment of hormone refractory disease. Resistance of tumour cells to anticancer therapies is generally viewed as a phenomenon almost exclusively determined by chromosomal defects and/or gene mutations. However, it is now well-documented that the local milieu of the bone metastases can also protect tumour cells from anticancer therapy- induced apoptosis, either independently or synergistically with resistance-related genetic alterations. A key determinant of this protection is the urokinase/plasmin cascade which modulates the local concentration of survival factors, such as insulin-like growth factor (IGF-1). The molecular pathways whereby this major growth and survival factor for prostate cancer cells exerts its anti-apoptotic effect on prostate cancer cells are discussed.
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PMID:Molecular biology and cellular physiology of refractoriness to androgen ablation therapy in advanced prostate cancer. 1177 38

Release of cytochrome c from mitochondria to cytosol has been identified as one of the central events of apoptosis. Direct injection of cytochrome c induces apoptosis in some but not in all cell types. We observed that LNCaP prostate cancer cells failed to undergo apoptosis induced by cytochrome c microinjections. Microinjection of cytochrome c with another mitochondrial protein, Smac, was sufficient to activate caspases, however. Smac is believed to function as a neutralizer of caspase inhibitors, and mass spectrometry analysis identified XIAP as a predominant Smac binding protein in LNCaP cells. These findings are consistent with a requirement for a release of Smac from mitochondria to enable caspase activation in prostate cells. Indeed, translocation of Smac from mitochondria to cytosol was observed in LNCaP cells that undergo apoptosis and was inhibited by epidermal growth factor, which is a survival factor for these cells. These results further emphasize the central role of mitochondria in the regulation of apoptosis in prostate cancer cells.
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PMID:Smac is required for cytochrome c-induced apoptosis in prostate cancer LNCaP cells. 1178 51

The local microenvironment at the sites of cancer metastases protects tumour cells from anticancer drug-induced apoptosis via mechanisms, such as soluble growth factors and cytokines. The concept of antisurvival factor (ASF) therapy as a component of anticancer treatments aims at neutralising the protective effect conferred upon cancer cells by the survival factor(s) derived by the local microenvironment, in order to enhance the sensitivity and/or reverse the resistance of tumour cells to other anticancer therapeutic strategies. Herein, we review the translation of this concept from ex vivo studies to clinical applications in the setting of prostate cancer refractory to androgen ablation (stage D3). At this stage, which predominantly involves bone metastases, insulin-like growth factor 1 (IGF-1) production (either growth hormone (GH)-dependent or GH-independent) can protect tumour cells from apoptosis, despite the significant suppression of androgens. The application of the ASF therapeutic concept involves the combination of dexamethasone (which suppresses GH-independent IGF-1) and somatostatin analogue (which suppresses endocrine, GH-dependent IGF-1) with the pro-apoptotic effect of the testicular androgen suppression by sustained use of LHRH analogues. In stage D3, patients who had failed anti-androgen withdrawal, chemotherapy and also had several other adverse prognostic features, the ASF-based combination achieved durable objective responses and major symptomatic improvement, paving the way for future applications of this approach. The ASF-based combination therapy illustrates a novel paradigm in cancer treatment: anti-tumour treatment strategies may not only aim at directly inducing cancer cell apoptosis, but can also target the tumour microenvironment and neutralise the protection it confers on metastatic cancer cells. The favourable toxicity profile of this therapeutic approach calls for its testing in a randomised controlled setting in metastatic prostate cancer and, conceivably, in other IGF-1-responsive malignancies.
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PMID:Combination of dexamethasone and a somatostatin analogue in the treatment of advanced prostate cancer. 1182 17


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