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)

Nude mice bearing xenografts of the androgen-independent human prostate-cancer cell line PC-3 were treated for 4 weeks with somatostatin analog RC-160, bombesin/gastrin-releasing peptide (GRP) antagonist (RC-3095), or the combination of both peptides. In the first experiment, treatment was started when the tumors measured approximately 10 mm3. Tumor volumes and weights were reduced by about 40% by RC-160 or RC-3095 administered by s.c. injections at doses of 100 micrograms/day/animal and 20 micrograms/day/animal respectively. The combination of RC-3095 with RC-160 did not further potentiate suppression of tumor growth, but histologically the ratio of apoptotic and mitotic indices was significantly higher in the groups treated with the combination than in the other groups. Serum gastrin levels were significantly reduced in all treated groups. Therapy with RC-160 or the combination also significantly decreased serum growth-hormone levels. Specific high-affinity binding sites for bombesin, somatostatin and epidermal growth factor (EGF) were found on the tumor membranes. Receptors for EGF were significantly down-regulated by treatment with RC-3095, RC-160 and a combination of both analogs. Tumors from mice treated with RC-160 showed a significant increase in maximal binding capacity for somatostatin as compared with control tumors, demonstrating the absence of down-regulation. In the second experiment, treatment was started when the tumors were well developed and measured approximately 90 mm3. No significant reduction in volume, weight and growth rate of tumors was found in the groups treated with RC-160 or RC-3095. Our results suggest that somatostatin analog RC-160 and bombesin/GRP antagonist RC-3095 can inhibit the growth of androgen-independent prostate cancer when the therapy is started at an early stage of tumor development.
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PMID:Effect of somatostatin analog RC-160 and bombesin/gastrin releasing peptide antagonist RC-3095 on growth of PC-3 human prostate-cancer xenografts in nude mice. 790 29

The effects of somatostatin analogue RC-160 and bombesin/gastrin releasing-peptide (GRP) antagonist RC-3095 were evaluated in Copenhagen rats bearing the anaplastic, androgen-independent Dunning R3327-AT-1 prostatic adenocarcinoma. In the first experiment, RC-160 was given in the form of microcapsules releasing 60 micrograms/day/rat. RC-3095 was administered from implanted Alzet osmotic minipumps liberating 100 micrograms/day/rat. After 32 days, tumor volumes and weights were significantly reduced by RC-160 as compared with the control group. Tumor doubling time in rats treated with RC-160 was significantly longer than in controls. Bombesin/GRP antagonist RC-3095 also significantly reduced tumor volume after 7 days of treatment, but after 18 days the inhibition in tumor volume was no longer significant. Tumor growth was not suppressed by castration. In the second experiment, 3-mm3 fragments of Dunning R-3327-AT-1 tumor were implanted orthotopically into the prostates of Copenhagen rats in order to evaluate the survival time of animals bearing this cancer during treatment with RC-160 released from Alzet osmotic minipumps at a dose of 100 micrograms/day/rat. Treatment with RC-160 significantly (P < 0.05) prolonged the mean survival time of rats by 5.3 days as compared to control animals. In both experiments, therapy with RC-160 significantly decreased serum growth hormone or insulin-like growth factor I levels. In the first experiment, receptor assays on R-3327-AT-1 tumor membranes showed high affinity binding sites for somatostatin, bombesin, and epidermal growth factor. At the end of the treatment, receptors for epidermal growth factor were significantly down-regulated by treatment with RC-160 but not with RC-3095. The binding capacity of bombesin receptors was reduced to nondetectable levels after the treatment with RC-3095. In cell cultures, high affinity binding sites for bombesin/GRP were found on intact Dunning R-3327-AT-1 cells, but receptors for somatostatin could not be detected. Proliferation of the AT-1 cell line was significantly inhibited by antagonist RC-3095. However, no effect on tumor cell growth in vitro was observed with analogue RC-160. Our results demonstrate that somatostatin analogue RC-160 and bombesin/GRP antagonist RC-3095 can inhibit the growth of the androgen-independent Dunning R-3327-AT-1 prostatic cancer in rats, although the remission produced by RC-3095 may be of short duration due to a down-regulation of bombesin receptors. Our work suggests the merit of further investigation as to whether these analogues can induce a possible delay in relapse and prolong survival in prostate cancer.
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PMID:Inhibitory effects of somatostatin analogue RC-160 and bombesin/gastrin-releasing peptide antagonist RC-3095 on the growth of the androgen-independent Dunning R-3327-AT-1 rat prostate cancer. 790 3

The effects of treatment with the luteinizing hormone-releasing hormone (LH-RH) antagonist SB-75 and agonist [D-Trp6] LH-RH were investigated in Copenhagen rats bearing the anaplastic, androgen-independent Dunning R-3327-AT-1 prostatic adenocarcinoma implanted orthotopically into the ventral lobes of prostate glands. The LH-RH antagonist SB-75 and the LH-RH agonist [D-Trp6] LH-RH were administered from osmotic minipumps and the survival time of animals bearing this cancer was evaluated. Treatment with SB-75 and [D-Trp6] LH-RH significantly prolonged the mean survival time of rats by 4.1 days and 4.5 days, respectively. In cell cultures, proliferation of the AT-1 cell line was strongly inhibited by the antagonist SB-75, but only a moderate suppression of tumor cell growth in vitro was observed with the agonist [D-Trp6] LH-RH. Receptor assays on Dunning R-3327-AT-1 tumor membranes showed high-affinity binding sites for LH-RH, epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1). Receptors for EGF were significantly down-regulated by treatment with SB-75. Therapy with SB-75 also decreased EGF levels in tumor tissue to non-detectable levels, as measured by specific RIA. Our results demonstrate that the LH-RH antagonist SB-75 and agonist [D-Trp6] LH-RH inhibit the growth of androgen-independent Dunning R-3327-AT-1 prostatic cancer in vivo and in vitro.
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PMID:Inhibitory effects of analogs of luteinizing hormone-releasing hormone on the growth of the androgen-independent Dunning R-3327-AT-1 rat prostate cancer. 792 4

This paper reviews basic and clinical aspects of human prostate cancer, with special regard to steroid hormones and growth factors, their receptors and the use of these tools in clinical practice. Unlike other endocrine-related tumours, such as breast and endometrial cancer, human prostatic carcinoma has distinctive features that crucially hinder its definition in terms of both biological potential and clinical course. Failure of androgen receptors to represent helpful discriminants for both prognosis and treatment of prostate cancer patients may depend upon methodological pitfalls and/or the heterogeneous composition of most tumour tissues. The former involve either technical problems (tissue sampling and storage, assay procedures) or biochemical and biological points (heterogeneity and functional integrity of steroid binding sites, subcellular and tissue distribution of steroid receptors). The latter mostly concern the unique feature of both normal and diseased prostate gland to present regional diversities in hormone sensitivity and steroid receptor content. Another important area of interest resides in the potential role played by stromal-epithelial interaction in the regulation of growth and function of prostate epithelial cells. In this respect, continued growth of androgen-dependent prostate cancer cells is achieved through intricate pathways where mesenchymal steroid-induced polypeptide growth factors may act in a paracrine/autocrine fashion to mediate androgen action on tumor epithelial cells. In particular, epidermal growth factor (EGF) and transforming growth factor-a (TGFa) may serve as androgen intermediaries in the proliferative control of prostate epithelial cells, but may also be involved in androgen-independent autocrine epithelial cell growth. Clinical correlations of androgen receptors in human prostatic carcinoma have been insofal disappointing. Biochemical or histochemical assays have failed to satisfactorily predict prognosis and response to endocrine therapies of patients. This recalls problems in both methodologies and tissue suitability and points to the need of prolonged follow-up studies wherein special care is placed in sampling conditions, identification of high-affinity sites of steroid binding and selection of threshold values for receptor concentrations. Assay of the EGF receptors might provide additional contribution for a deeper inspection of the biological nature of prostate tumour tissues and help in selecting more appropriate individual-based therapeutic strategies.
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PMID:Steroid receptors in prostate cancer tissues and cells: pathophysiology, problems in methodology, clinical value and controversial questions. 800 81

Amphiregulin is a heparin-binding epidermal growth factor (EGF)-related peptide that binds to the EGF receptor (EGF-R) with high affinity. In this study, we report a role for amphiregulin in androgen-stimulated regulation of prostate cancer cell growth. Androgen is known to enhance EGF-R expression in the androgen-sensitive LNCaP human prostate carcinoma cell line, and it has been suggested that androgenic stimuli may regulate proliferation, in part, through autocrine mechanisms involving the EGF-R. In this study, we demonstrate that LNCaP cells express amphiregulin mRNA and peptide and that this expression is elevated by androgenic stimulation. We also show that ligand-dependent EGF-R stimulation induces amphiregulin expression and that androgenic effects on amphiregulin synthesis are mediated through this EGF-R pathway. Parallel studies using the estrogen-responsive breast carcinoma cell line, MCF-7, suggest that regulation of amphiregulin by estrogen may also be mediated via an EGF-R pathway. In addition, heparin treatment of LNCaP cells inhibits androgen-stimulated cell growth further suggesting that amphiregulin can mediate androgen-stimulated LNCaP proliferation. Together, these results implicate an androgen-regulated autocrine loop composed of amphiregulin and its receptor in prostate cancer cell growth and suggest that the mechanism of steroid hormone regulation of amphiregulin synthesis may occur through androgen upregulation of the EGF-R and subsequent receptor-dependent pathways.
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PMID:Epidermal growth factor receptor-dependent stimulation of amphiregulin expression in androgen-stimulated human prostate cancer cells. 804 25

Nude mice bearing xenografts of the androgen-independent human prostate cancer DU-145 were treated for 4-5 weeks with somatostatin analog RC-160 or the bombesin/gastrin-releasing peptide (GRP) antagonist RC-3095. Tumor growth in animals treated with somatostatin analog RC-160 at a dose of 100 micrograms/day s.c. was significantly inhibited within 14 days of the start of the experiment. At necropsy, in mice given RC-160, tumor weight and volume were significantly decreased compared with control mice. Treatment with RC-3095 at a dose of 20 micrograms/day s.c. also suppressed tumor growth, the inhibition being significant after 2 weeks, but the reduction in tumor volume and weight was smaller than that produced by RC-160. Therapy with RC-160 significantly decreased serum growth hormone and gastrin levels. Specific binding sites for bombesin, somatostatin and epidermal growth factor (EGF) were found in the DU-145 tumor membranes. Receptors for EGF were significantly down-regulated after therapy with RC-3095 and RC-160. The finding that somatostatin analog RC-160 and bombesin/GRP antagonist RC-3095 inhibit the growth of androgen-independent prostate tumors in mice might be of practical importance for human prostate cancer therapy.
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PMID:Somatostatin analog RC-160 and bombesin/gastrin-releasing peptide antagonist RC-3095 inhibit the growth of androgen-independent DU-145 human prostate cancer line in nude mice. 810 19

Androgens affect growth of the prostate gland and many prostate cancers. Androgens could mediate their mitogenic effects on prostate cells by an autocrine loop involving epidermal growth factor (EGF) and transforming growth factor (TGF)-alpha that bind to the EGF/TGF-alpha receptor. We examined the effects of 5 alpha-dihydrotestosterone (DHT) and testosterone (T), EGF, and EGF-alpha on cell proliferation and 3H-thymidine incorporation in an androgen-dependent human prostate cancer cell line, ALVA101, in serum-free medium. The regulation of TGF-alpha and EGF/TGF-alpha receptor messenger RNA (mRNA) levels were determined by Northern blot analysis and EGF/TGF-alpha receptor protein by immunoblot. After 24 h of treatment of ALVA101 cells with DHT (10(-8) M) or T (10(-8) M), TGF-alpha mRNA levels increased 3- and 2.5-fold, respectively, and EGF/TGF-alpha receptor mRNA levels 2- and 1.5-fold, respectively. Cell numbers increased at day 5 in response to 10(-8) M DHT (18%, P < 0.01), 10(-8) M T (15%, P < 0.01), 20 ng/ml EGF (16%, P < 0.01), and 50 ng/mL TGF-alpha (34%, P < 0.01). DHT combined with TGF-alpha or T combined with EGF increased cell number 43% and 40% above control, respectively (P < 0.01 vs. DHT, P < 0.05 vs. TGF-alpha, T, EGF alone). The anti-EGF/TGF-alpha receptor antibody (528) blocked the cell proliferation induced by either DHT or TGF-alpha. We conclude that DHT and T stimulate synthesis of TGF-alpha and EGF/TGF-alpha receptor mRNAs and EGF/TGF-alpha receptor content in ALVA101 cells. This mitogenic effect of androgen on ALVA101 cells may involve TGF-alpha and the EGF/TGF-alpha receptor autocrine loop.
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PMID:Androgens regulate proliferation of human prostate cancer cells in culture by increasing transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF)/TGF-alpha receptor. 826 29

Prostate adenocarcinoma, the most common tumor occurring among North American men, preferentially metastasizes to bone, where it characteristically forms osteoblastic lesions. The following growth regulatory factors are expressed in some human prostate cancers and/or established cell lines: epidermal growth factor (EGF), transforming growth factor alpha, transforming growth factor beta, basic fibroblast growth factor (bFGF), and insulin-like growth factor. Some of these, especially EGF, bFGF, and TGF-beta, are also implicated in growth regulation in normal and benign hyperplastic prostates. Although evidence from in vitro study of the small number of prostate cell lines available demonstrates that these growth regulatory pathways are exploited by some of these cells, direct in vivo evidence is limited. The development of human prostate cancer cell lines which grow and metastasize in immune-deficient rodents is an advance which now permits experimental analysis of the role of these growth factors in prostatic metastasis, particularly to bone. The progression and metastasis of human prostate cancer results from the complex interactions of multiple growth factors, androgens, and cellular communication, which form a dynamic network. Continued progress in the study and treatment of this disease will require new conceptual frameworks as well as successful application of the techniques of molecular and cellular biology.
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PMID:Growth factors and their receptors as determinants in the proliferation and metastasis of human prostate cancer. 828 14

Elevated levels of epidermal growth factor (EGF) and epidermal growth factor receptor (EGF-R) have been demonstrated in prostate cancer cell lines and clinical specimens suggesting a role for polypeptide growth factors in prostate tumor cell growth and invasion. To more clearly define the role of EGF in prostate cancer invasion, we undertook a series of studies utilizing the PC3 prostate cancer cell line, an aggressive, hormone-independent cell line derived from a metastatic lesion. No statistical differences were noted in the growth of PC3 cells under serum-free conditions when EGF (10(-10) M-10(-8) M) or monoclonal anti-EGF-R antibody (10(-11) M-10(-8) M) were added. Utilizing the Boyden chamber microinvasion assay, EGF supplemented cells demonstrated a statistically significant augmentation in invasion (P < 0.05) when compared to control cells at each time point in the study. With increasing length of exposure to EGF, the number of concentrations that produced significant invasion increased: day 1 (10(-8) M), day 3 (10(-8), 10(-9) M), and day 5 (10(-7), 10(-8), 10(-10) M). Northern blot analysis of EGF supplemented cells revealed an increase in expression of urokinase plasminogen activator (uPA) RNA, a serine protease involved in the regulation of pericellular proteolysis and membrane degradation. Protein analysis confirmed these findings. Statistically significant inhibition of invasion by anti-uPA antibodies was demonstrated for EGF-stimulated and PC3 control cells. Our results demonstrate that certain concentrations of EGF augment invasion in the PC3 cell line. This enhancement of invasion occurs in part by an overproduction of uPA, an extracellular protease. These findings suggest that the autocrine production of EGF may potentiate tumor cell invasion.
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PMID:Effect of epidermal growth factor on prostate cancer cell line PC3 growth and invasion. 829 Mar 89

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


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