Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Epidermal growth factor receptor (EGFR) and HER-2 are associated with a poor prognosis in various cancers, including prostate cancer. Inhibition of these receptors may provide a treatment for hormone-refractory prostate cancer. The presence of HER-2 (Western blot) and EGFR (5830 fmol/mg protein, ligand-binding assay) was assessed in the hormone-refractory human prostate cancer cell line, DU-145. Cells were exposed to the selective EGFR-TKI (EGFR tyrosine kinase inhibitor) gefitinib ('Iressa; ZD1839) and/or the HER-2-targeted monoclonal antibody trastuzumab ('Herceptin'), for 96 h. Irradiation (RX) at 6 Gy the dose causing 50% growth inhibition, was applied 48 h after the start of drug treatment. There was a dose-related effect on cell survival for both ZD1839 and trastuzumab treatments. Combining ZD1839 and trastuzumab led to less than additive effects on cell survival. Chou and Talalay representations further characterised this less than additive effect on cell survival. The application of ZD1839 led to a marked elevation in the level of the negative regulator of cell division, p27. The ZD1839-trastuzumab combination had less of an impact on p27 expression compared with the effect of ZD1839 treatment alone. The lowest expression of the apoptotic-related protein, Bax, was observed in the presence of the drug combination. There was a significant interaction (synergism) between RX and either ZD1839 or trastuzumab treatments. In contrast, the drug combination with RX resulted in antagonistic cytotoxic effects. These results indicate an antagonistic interaction between EGFR and HER-2 targeting and provide molecular mechanisms supporting this observation. Data from DU-145 cells suggest that dual targeting of EGFR and HER-2 may be inappropriate for the treatment of hormone-refractory prostate cancer, especially in the context of their combination with RX.
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PMID:Dual HER 1-2 targeting of hormone-refractory prostate cancer by ZD1839 and trastuzumab. 1557 68

Recent advances in cancer therapy have resulted in the development of drugs that target mechanisms involved in neoplastic change and angiogenesis. One example is gefitinib ('Iressa', ZD1839), an orally-active epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that blocks EGFR signaling in vitro, thereby inhibiting the growth, proliferation and survival of many solid tumors. Clinical trial data show that gefitinib monotherapy is generally well tolerated in patients with a wide range of tumor types (including lung, head and neck, colon, breast, and prostate cancers). The most common adverse events (AEs) were mild and reversible skin and gastrointestinal disorders (National Cancer Institute common toxicity criteria grade 1/2). Few drug-related grade 3/4 skin and gastrointestinal disorders were observed, and drug-related hematologic AEs were uncommon. The clinical benefit of gefitinib in non-small-cell lung cancer (NSCLC), head and neck, colon, breast, and prostate cancer is being investigated, as antitumor activity has been observed in a range of solid tumors, including NSCLC. In two large phase II NSCLC trials (IDEAL ['Iressa' Dose Evaluation in Advanced Lung Cancer] 1 and 2) objective tumor responses of 18.4% and 11.8%, and disease control rates (complete and partial responses plus stable disease) of 54.4% and 42.2%, respectively, were seen in patients given 250 mg/day gefitinib. Additionally, disease-related symptoms improved in 40.3% and 43.1% of patients, and improved quality of life was experienced by 23.9% and 34.3% patients in IDEAL 1 and 2, respectively. Furthermore, the majority of patients who had an objective response also experienced symptom improvement. Gefitinib has been approved for the treatment of advanced NSCLC in Japan, the USA, and other countries. This review discusses the potential of gefitinib in a wide range of solid tumors. 'Iressa' is a trademark of the AstraZeneca group of companies.
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PMID:Gefitinib (Iressa, ZD1839): a novel targeted approach for the treatment of solid tumors. 1558 98

De novo and acquired resistance to the anti-tumour drug gefitinib (ZD1839; Iressa), a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has been reported. We have determined whether signalling through the IGF-I receptor (IGF-1R) pathway plays a role in the gefitinib-acquired resistance phenotype. Continuous exposure of EGFR-positive MCF-7-derived tamoxifen resistant breast cancer cells (TAM-R) to 1 microM gefitinib resulted in a sustained growth inhibition (90%) for 4 months before the surviving cells resumed proliferation. A stable gefitinib-resistant subline (TAM/TKI-R) was established after a further 2 months and this showed no detectable basal phosphorylated EGFR activity. Compared with the parental TAM-R cells, the TAM/ TKI-R cells demonstrated (a) elevated levels of activated IGF-1R, AKT and protein kinase C (PKC)delta, (b) an increased sensitivity to growth inhibition by the IGF-1R TKI AG1024 and (c) an increased migratory capacity that was reduced by AG1024 treatment. Similarly, the EGFR-positive androgen-independent human prostate cancer cell line DU145 was also continuously challenged with 1 microM gefitinib and, although substantial growth inhibition (60%) was seen initially, a gefitinib-resistant variant (DU145/TKI-R) developed after 3 months. Like their breast cancer counterparts, the DU145/TKI-R cells showed increases in the levels of components of the IGF-1R signalling pathway and an elevated sensitivity to growth inhibition by AG1024 compared with the parent DU145 cell line. Additionally, DU145/TKI-R cell migration was also decreased by this inhibitor. We have therefore concluded that in breast and prostate cancer cells acquired resistance to gefitinib is associated with increased signalling via the IGF-1R pathway, which also plays a role in the invasive capacity of the gefitinib-resistant phenotype.
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PMID:Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. 1561 53

Recent evidence indicates that androgen-sensitive prostate cancer cells have a less malignant phenotype characterized by reduced migration and invasion. We investigated whether the presence of the androgen receptor could affect EGFR-mediated signaling by evaluating autotransphosphorylation of the receptor as well as activation of the downstream signaling pathway PI3K/AKT. Immunoprecipitation studies demonstrated a reduction of EGF-induced tyrosine phosphorylation of EGFR in PC3-AR cells. In addition, EGF-stimulated PI3K activity, a key signaling pathway for invasion of these cells, was decreased in PC3-AR cells and further reduced by treatment with R1881, indicating decreased functionality of EGFR. Our results suggest that the expression of androgen receptors by transfection in PC3 cells confers a less malignant phenotype by interfering with EGFR autophosphorylation and signaling leading to invasion in response to EGF. We used the selective tyrosine kinase inhibitor of the EGFR gefitinib (also known as Iressa or ZD1839) to further investigate the role of EGFR in the invasion and growth of PC cells. We demonstrate that in the androgen-insensitive cell lines PC3 and DU145 this compound was able to decrease in vitro invasion of Matrigel by inhibiting EGFR autotransphosphorylation and subsequent PI3K activation. Gefitinib may be useful in the treatment of androgen-independent prostate cancer to limit not only the proliferation but also the invasion of these tumors.
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PMID:Signaling mechanisms that mediate invasion in prostate cancer cells. 1565 Feb 53

Introduction of novel diagnostic methods and multimodal therapy has resulted in about 70% probability of cure of childhood neoplasms. However, treatment results of some neoplastic diseases in children, including chronic myelogenous leukemia (CML) still remain unsatisfactory. The only chance of cure remains allogeneic hematopoietic stem cell transplantation, however availability of transplantation is still low as a limited number of donors is available. In neoplastic diseases in which treatment results remain poor, intensification of treatment components (chemotherapy, radiotherapy) did not succeed in improving the treatment results. In recent years no improvement was made in gene therapy. With introduction of new drugs that selectively inhibit mechanisms of maturation and proliferation of cancer cells, new hope has arisen. In our paper we present the mechanism of action of imatinib, the tyrosine kinase inhibitor which was employed in the treatment of CML and gastrointestinal stromal tumors. Currently, there are several ongoing studies assessing the efficacy of this novel drug in the therapy of brain tumors, neuroblastoma, lung and prostate cancer.
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PMID:[Perspectives in the use of imatinib in the treatment of childhood cancers]. 1568 56

Prostate cancer is the second highest cause of cancer-related deaths of men in the US. Signal transducers and activators of transcription (STATs) proteins are a small family of latent cytoplasmic transcription factors that act downstream of Janus kinase (JAK) activation and mediate intracellular signaling from a wide variety of cytokines, growth factors, and hormones. Aberrant activation of STAT3 has been implicated in the progression of many human carcinomas, including prostate cancer. Previously, we have characterized a novel tyrosine kinase inhibitor peptide, Tkip, that is a mimetic of suppressor of cytokine signaling 1 (SOCS-1). Similar to SOCS-1, Tkip binds to the autophosphorylation site of JAK2 and inhibits phosphorylation of STAT1alpha. In this study, we determined the inhibitory effects of Tkip on the human prostate cancer cell lines DU145 and LNCaP. Tkip inhibited cellular proliferation of both DU145 and LNCaP cells, with a slightly greater antiproliferative effect on DU145 cells. Cell cycle analysis using flow cytometry showed Tkip blockage of progression into the S phase of the cell cycle. Tkip also inhibited constitutive (DU145) and IL-6-induced (LNCaP) activation of STAT3, consistent with the fact that STAT3 activation is mediated by JAK2. Tkip also slightly reduced the levels of cyclin D1, an important regulator of cell cycle progression into S phase, in DU145 and LNCaP cancer cell lines. These data describe a potentially important therapeutic that targets both constitutive and IL-6-induced STAT3 activation in human prostate cancer cell lines.
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PMID:A SOCS-1 peptide mimetic inhibits both constitutive and IL-6 induced activation of STAT3 in prostate cancer cells. 1568 10

Progression from an androgen-dependent to an androgen-independent state often occurs in patients with prostate cancer (PCa) who undergo hormonal therapy. We have investigated whether inhibition of the epidermal growth factor receptor (EGFR) signaling pathway affects the antitumor effect of a nonsteroidal antiandrogen. Gefitinib (Iressa), an EGFR tyrosine kinase inhibitor, and bicalutamide (Casodex), a nonsteroidal antiandrogen [androgen receptor (AR) antagonist], were administered alone and in combination to AR-positive human PCa cell lines. FACS analysis showed lower EGFR expression levels on AR-positive cells (LNCaP, CWR22, CWR22R 2152 and AR-transfected DU145 cell lines) compared with AR-negative cells (DU145, PC3 and TSU-Pr1). Moreover, in AR-transfected DU145 cells, chronic treatment with bicalutamide increased EGFR expression to levels similar to androgen-independent DU145 cells. All AR-positive PCa cell lines were sensitive to gefitinib (IC50 = 0.1-0.6 microM), whereas higher concentrations of bicalutamide were needed to reduce AR-positive PCa cell line proliferation (IC50 = 0.8-2.0 microM). Low doses of gefitinib increased the antitumor effects of bicalutamide by strongly reducing the IC50 of bicalutamide (approximately 10-fold). Similarly, bicalutamide increased the antiproliferative effects of gefitinib by reducing the IC50 of gefitinib (approximately 5-fold). Taken together, our data suggest that in androgen-dependent cell lines, addition of gefitinib in combination with bicalutamide results in concurrent dual inhibition of AR and EGFR/HER2 pathways. This causes a significant delay in the onset of EGFR-driven androgen independence.
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PMID:Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro. 3109 26

Advanced prostate cancer invariably recurs despite androgen deprivation therapy. The androgen receptor (AR) likely plays a key role in this progression and in the continued survival and proliferation of prostate cancer cells in the low androgen environment. Cross-talk with growth factor receptors, such as epidermal growth factor receptor (EGFR) family, has been postulated as a potential mechanism to activate AR in recurrent prostate cancer. We have investigated the role of HER-2/neu (ErbB-2) tyrosine kinase in AR function by characterizing the effect of inhibiting endogenous HER-2 activity in LNCaP cells. We used two independent methods, expression of intracellular single-chain antibody against HER-2 and treatment with a novel dual EGFR/HER-2 kinase inhibitor GW572016 (lapatinib). Expression of intracellular HER-2 antibody scFv-5R and treatment with GW572016 inhibited HER-2 signaling. This HER-2 inhibition led to impairment of AR-mediated functions, such as androgen-stimulated growth and the induction of endogenous prostate-specific antigen (PSA) mRNA and protein. Androgen-stimulated recruitment of AR and histone acetylation at the androgen responsive enhancer of the PSA gene, detected by chromatin immunoprecipitation analysis, were impaired by HER-2 inhibition. GW572016 was more potent in its ability to inhibit PSA expression and AR recruitment and histone acetylation than the EGFR-selective kinase inhibitor ZD1839 (gefitinib), consistent with the HER-2 kinase playing the major role in AR regulation. These results show that HER-2 signaling is required for optimal transcriptional activity of AR in prostate cancer cells and suggest that HER-2 inhibition may provide a novel strategy to disrupt AR function in prostate cancer.
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PMID:Inhibition of HER-2/neu kinase impairs androgen receptor recruitment to the androgen responsive enhancer. 1583 75

Urokinase-type plasminogen activator (uPA) seems to be an important protease in prostate cancer invasion, and tyrosine phosphorylation is thought to play a role in the regulation of its production. The amount of uPA was measured with a synthetic peptide substrate after treatment with various concentrations of tyrosine kinase inhibitors (TKI). The effect on proliferation and apoptosis was also assayed. Non-toxic levels of genistein or the tyrphostin AG 490 produced up to 50% reduction of the uPA production in PC-3 and DU-145. The tyrphostins AG 1296 and AG 1478 inhibited uPA production in PC-3 cells, whereas DU-145 showed a slight increase of uPA production. TKI neither induced any detectable apoptosis, nor was there any reduction in proliferation rate. TKI can profoundly modify the production of uPA in prostatic cancer cells, thus indicating their possible use as suppressors of the invasive phenotype. The therapeutic potential of TKI warrants further investigation.
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PMID:Inhibitors of tyrosine kinase inhibit the production of urokinase plasminogen activator in human prostatic cancer cells. 1601 59

We have previously shown that concentrations of 1alpha,25-dihydroxyvitamin D(3) (1,25D) that induce G(0)/G(1) cell cycle arrest in androgen-dependent LNCaP prostate cancer cells also decrease expression of c-Myc, a proto-oncogene that stimulates progression from G(1) to S phase of the cell cycle. Since both c-Myc expression and cell cycle progression are regulated by tyrosine kinase activation, we examined the ability of 1,25D to alter tyrosine kinase signaling in LNCaP cells and the androgen-independent LNCaP C81 (C81 LN) cell line. 1,25D selectively reduced protein tyrosine phosphorylation within both the LNCaP and C81 LN cells. This reduction in tyrosine kinase signaling appears to result from elevated levels of cellular prostatic acid phosphatase (PAcP). Western blots and biochemical assays revealed 1,25D increases the level of active PAcP in both cell lines. In addition, 1,25D decreased tyrosine phosphorylation of HER-2, an EGFR family member inactivated by PAcP, and the HER-2 downstream adaptor protein p52 Shc in C81 LN cells. Inhibition of HER-2 signaling by AG825 reduces growth of C81 LN cells and the parental LNCaP cells. These data therefore suggest that 1,25D-mediated decreases in LNCaP and C81 LN cell growth are in part due to decreases in tyrosine kinase signaling that result from up-regulation of PAcP.
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PMID:Vitamin D receptor agonists induce prostatic acid phosphatase to reduce cell growth and HER-2 signaling in LNCaP-derived human prostate cancer cells. 1607 55


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