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)

Recently, we have described a novel gene, DD3, which is one of the most prostate cancer-specific genes described to date (Bussemakers, M. J. G., van Bokhoven, A., Verhaegh, G. W., Smit, F. P., Karthaus, H. F. M., Schalken, J. A., Debruyne, F. M. J., Ru, N., and Isaacs, W. B. (1999) Cancer Res. 59, 5975-5979). The prostate cancer-specific expression of DD3 indicates that the DD3 gene promoter is a promising tool for the treatment of prostate cancer. To identify the promoter elements that are responsible for the prostate cancer-specific expression of DD3, we have isolated and characterized the DD3 promoter. Sequence analysis of the DD3 5'-flanking region was performed and several promoter-human growth hormone reporter constructs were prepared, which were transiently transfected in the DD3-positive cell line LNCaP and several DD3-negative cell lines. Using a 500-base pair DD3 promoter construct, we could detect promoter activity in LNCaP cells, which was not affected by increasing the size of the constructs. Truncated constructs, however, showed an increased transcriptional activity, suggesting the presence of a silencer that negatively regulates the expression of DD3. DNase-I footprint analysis, using nuclear extracts from LNCaP cells, revealed the presence of three DNase-I-protected areas within the DD3 proximal promoter. We show that the high mobility group I(Y) protein binds to one of the DNase-I-protected areas and recruits another, yet unidentified, protein to the DD3 promoter in LNCaP cells.
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PMID:Isolation and characterization of the promoter of the human prostate cancer-specific DD3 gene. 1098 8

The use of peptide analogs in the therapy of prostate cancer is reviewed. The preferred primary treatment of advanced androgen-dependent prostate cancer is presently based on the use of depot preparations of LH-RH agonists. This treatment is likewise recommended in patients with rising PSA levels after surgery or radiotherapy. LH-RH agonists with or without antiandrogens can be also utilized prior to or following various local treatments in patients with clinically localized prostate cancer and at high risk for disease recurrence. LH-RH antagonists like Cetrorelix are in clinical trials. However, most patients with advanced prostatic carcinoma treated by any modality of androgen deprivation eventually relapse. Treatment of relapsed androgen-independent prostate cancer remains a major challenge, but new therapeutic modalities are being developed based on antagonists of growth hormone-releasing hormone (GH-RH) and bombesin, which inhibit growth factors or their receptors. Another approach consists of cytotoxic analogs of LH-RH, bombesin, and somatostatin containing doxorubicin or 2-pyrrolinodoxorubicin, which can be targeted to receptors for these peptides found in prostate cancers and their metastases. These cytotoxic analogs inhibit growth of experimental androgen-dependent or -independent prostate cancers and reduce the incidence of metastases. A rational therapy with peptide analogs could be selected on the basis of receptors present in biopsy samples. The approaches based on peptide analogs should result in a more effective treatment for prostate cancer.
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PMID:Peptide analogs in the therapy of prostate cancer. 1102 15

Interleukin (IL)-15 is a pleiotropic cytokine that is important for innate and adaptive immune cell homeostasis. The expression of IL-15 protein is controlled by posttranscriptional mechanisms. Here, we constructed a human IL-15 expression vector consisting of the human IL-2 signal peptide, the human IL-15 mature peptide-coding sequences, and an out-of-frame human growth hormone gene. Human prostate cancer cells, PC-3, transfected with this highly secretable form of the IL-15 gene, successfully secreted abundant bioactive IL-15 protein. In nude mice, the growth of PC-3 cells producing IL-15 was remarkably retarded. NK cell-depletion using anti-asialo GM1 antibody restored tumorigenicity. Histologically, tumors derived from IL-15-producing PC-3 cells contained necrotic areas with high apoptotic index. Splenocytes incubated with supernatant of transfectants killed target PC-3 cells and expressed a significantly high level of mIFN-gamma mRNA. These observations suggest that NK cell-mediated, anti-tumor effects of IL-15 could provide a potential rationale for gene therapy of prostate cancer.
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PMID:NK cell-mediated anti-tumor immune response to human prostate cancer cell, PC-3: immunogene therapy using a highly secretable form of interleukin-15 gene transfer. 1131 Aug 38

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

This study has examined the expression of two new facets of the growth hormone axis, the growth hormone secretagogue receptor (GHS-R) and its recently identified putative natural ligand ghrelin, in prostate cancer cells. GHS-R 1a and 1b isoforms and ghrelin mRNA expression were detected by RT-PCR in the ALVA-41, LNCaP, DU145 and PC3 prostate cancer cell lines. A normal prostate cDNA library expressed GHS-R1a, but not the 1b isoform or ghrelin. Immunohistochemical staining for the GHS-R 1a isoform and ghrelin was positive in the four cell lines studied. PC3 cells showed increased cell proliferation in vitro in response to ghrelin to levels 33% above untreated controls, implying a potential tumour-promoting role for ghrelin in this tissue. This study is the first to demonstrate the co-expression of the GHS-R and ghrelin in prostate cancer cells. It is also the first study to provide evidence that a previously unrecognised autocrine/paracrine pathway involving ghrelin, that is capable of stimulating growth, exists in prostate cancer.
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PMID:Expression and action of the growth hormone releasing peptide ghrelin and its receptor in prostate cancer cell lines. 1187 17

Vasoactive intestinal peptide (VIP) stimulates the proliferation and invasiveness of malignant prostatic cells. Receptors for VIP and the closely related growth hormone-releasing hormone (GH-RH) show considerable homology and are found in prostatic and other carcinomas. Among various analogs of GH-RH synthesized, JV-1-52 is a non-selective VIP/GH-RH antagonist, whereas JV-1-53 is a VIP antagonist devoid of GH-RH antagonistic effect. In our study, nude mice bearing PC-3 human androgen-independent prostate carcinomas were treated with JV-1-52 or JV-1-53 (20 microg/day, s.c.) for 28 days. Both antagonists produced a similar reduction in tumor volume (62-67%, p < 0.01) and tumor weight (59-62%; p < 0.05) vs. controls and extended tumor doubling-time from 9.1 to about 16 days (p < 0.05). To investigate the mechanisms involved, in another study we compared the effects of JV-1-53 with those of somatostatin analog RC-160. VIP antagonist JV-1-53 reduced tumor weight by 67% (p < 0.01) and suppressed the expression of mRNA for c-fos and c-jun oncogenes by about 34% (p < 0.05), without affecting serum levels of insulin-like growth factor-I (IGF-I). In contrast, RC-160 (50 microg/day) reduced serum IGF-I by 19% (p < 0.05), but did not significantly decrease tumor weight. mRNA for VIP and high affinity receptors for VIP were detected on PC-3 tumors. Our results suggest that VIP/GH-RH antagonists can inhibit the growth of androgen-independent prostate cancer by abrogating the autocrine/paracrine mitogenic stimuli of VIP. The ability of GH-RH antagonists to block tumoral VIP receptors, in addition to GH-RH receptors, could be potentially beneficial for prostate cancer therapy.
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PMID:Inhibition of PC-3 human prostate cancers by analogs of growth hormone-releasing hormone (GH-RH) endowed with vasoactive intestinal peptide (VIP) antagonistic activity. 1192 Jun 25

Progress in the understanding of the action of exogenous testosterone has diminished many of the concerns that existed regarding its safety. The major interest is now focused on the effects of androgen supplementation on the prostate gland. Many such concerns have been addressed but others remain to be fully elucidated. It is well established that hypogonadal men receiving adequate androgen therapy develop a prostate with a volume similar to what would be expected from their eugonadal counterparts. Androgen therapy results in modest elevations in the PSA and minor changes in flow parameters. Prostate cancer, on the other hand, remains the most prominent of the safety concerns. Although there is no evidence that normal levels of testosterone promote the development of cancer of the prostate, it is clear that the administration of testosterone enhances a pre-existing prostatic malignancy. Androgen supplementation studies have been, in most cases, of short duration and lacked a control cohort. The current evidence does not support the view that appropriate treatment of hypogonadal elderly men with androgens has a causal relationship with prostate cancer. Larger experience, however, is needed. The same criteria applies to the use of other hormones such as dehydrotestosterone, dehydroepiandrosterone follicle stimulating and growth hormone. A set of recommendations regarding androgen replacement therapy and prostate safety is proposed.
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PMID:Androgen replacement therapy and prostate safety. 1207 96

With prolonged life expectancy, men and women can expect to live one-third of their lives with some form of hormone deficiency. The ageing male, in particular, has the added problem of developing urological diseases, such as benign prostatic hyperplasia (BPH), prostate cancer, continence disorders and erectile dysfunction. When discussing age-related problems, it is often difficult to separate and to distinguish between the natural ageing process, ageing amplifiers and an acute or chronic illness, or inter-current diseases. Partial endocrine deficiencies of ageing are associated with a decrease in the peripheral levels of testosterone, dehydroepiandrosterone (DHEA), DHEA sulphate (DHEA-S), growth hormone, insulin-like growth factor and melatonin. There is also a concomitant increase in luteinising hormone and follicle stimulating hormone. The concentration of free biologically active testosterone is lowered further by an increase in sex hormone binding globulin (SHBG). Hormonal changes in the ageing male are associated with changes in the body mass index, osteoporosis, sleep and mood disorders. A number of testosterone replacement therapies are available. These therapies should maintain physiological levels not only of serum testosterone, but also of its metabolites, including dihydrotestosterone (DHT) and estradiol. Men on testosterone therapy should be monitored at 3-month intervals during the first year of use and, thereafter, at 1-year intervals if they are stable. The association of testosterone replacement with development of prostate cancer has not been determined.
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PMID:The ageing male. 1208 88

Prostate cancer is a significant cause of morbidity and mortality in Western males. While it is known that androgens play a central role in prostate cancer development and progression, other hormones and growth factors are also involved in prostate growth. Insulin-like growth factor-I (IGF-I) plasma levels have been associated with prostate cancer risk, and growth hormone (GH), a major factor regulating IGF levels, also appears to have a role in prostate cancer cell growth. Most significantly, GH has been shown to increase the rate of cell proliferation in prostate cancer cell lines. We have now demonstrated the co-expression of GH and GH receptor (GHR) mRNA isoforms in the ALVA41, PC3, DU145, LNCaP prostate cancer cells by reverse transcription polymerase chain reaction. Sequence analysis has confirmed that these cell lines express the pituitary form of GH mRNA and also the placental mRNA isoform. These prostate cancer cell lines also express the full-length mRNA for the GHR and the exon 3 deleted isoform. We have also demonstrated the presence of GH and GHR proteins in these cell lines by immunohistochemistry. GH expression has not been described previously in human prostate cancer cells. The co-expression of GH and its receptor would enable an autocrine-paracrine pathway to exist in the prostate that would be capable of stimulating prostate growth, either directly via the GHR or indirectly via IGF production. The GH axis in the prostate could therefore be an important additional target for the future development of prostate cancer therapies.
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PMID:Co-expression of GH and GHR isoforms in prostate cancer cell lines. 1217 50

Due to the characteristics of the luteal phase of the ovarian cycle in the dog, which spans a prolonged time period, this species is a suitable model to study the role of progestins in both normal morphogenic and abnormal tumorigenic processes in the mammary gland. It has been convincingly shown that progestins, including endogenous progesterone, induce the synthesis of growth hormone (GH) in the normal and the tumorous canine mammary gland. The growth hormone receptor (GHR) is also expressed in normal and tumorous canine mammary tissues and in this concise overview we highlight recent advances in our understanding of the significance of the GH/GHR system for mammary gland (patho)biology. In an attempt to unravel the cellular and molecular mechanisms associated with the GH/GHR system, we were able to show that both GH and GHR are differentially expressed in normal canine mammary tissues. Maximum expression of both GH and GHR occurs during the proliferation phase of the tissue, which links the progestin-induced mammary GH synthesis to the progestin-associated proliferation of epithelial cells in the mammary gland. Expression of the GH/GHR system is also present in most canine mammary tumors, albeit that GHR expression may be downregulated in undifferentiated mammary carcinomas. Upon GH stimulation of the GHR-positive CMT-U335 canine mammary tumor cell line, the transcription factors STAT5A and STAT5B become phosphorylated on their tyrosine residues, which is likely to reflect the significance of mammary GH in vivo. Molecular analysis of the canine mammary GHR transcripts by RT-PCR provided evidence for normal and alternative processing of the GHR primary transcript encoding the full-length plasma membrane GHR and at least four putative GH binding proteins (GHBPs), respectively. The translation products from the alternatively spliced GHR transcripts indicate an intact N-terminal ligand binding domain and an unique C-terminal portion, lacking the transmembrane domain and cytoplasmic tail. Thus, these proteins are considered to be able to bind GH, but have lost their signaling potential. The exact biological role of these GHBPs remains to be established, but GHBPs may have a transport function in the endocrine route, regulate the level of biologically available GH locally, or dominant-negatively influence the full-length plasma membrane GHR. In dog mammary cancer specimens strongly reduced levels of alternatively spliced GHR transcripts were found compared to the non-malignant mammary tissue. Notably, expression of both GH and GHR in mammary cancer cells is not restricted to dogs. Recent experiments generated evidence for GH and GHR expression in human breast cancer cells, and also in human prostate cancer cells, which represents another highly prevalent hormone-sensitive human malignancy. In agreement with our findings in the dog, the expression of the hGH-N gene in human mammary cancer cells seemed to correlate positively with their progesterone receptor status, which warrants, in our opinion, a reconsideration of the role of progestins in breast cancer of women. In human prostate cancer cells four different hGH-N transcripts were detected, which encode classical 22 kDa GH and GH-related proteins. Consistent with the findings on the canine GHR, different GHR transcripts in human mammary cancer cells and prostate cancer cells were detected encoding the full-length plasma membrane GHR and putative GHBPs.
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PMID:Morphogenic and tumorigenic potentials of the mammary growth hormone/growth hormone receptor system. 1243 8


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