UMLS:C0025202 - FACTA Search

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Query: UMLS:C0025202 (melanoma)
69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor (VEGF) is an important mediator of tumor-associated angiogenesis, and consequently it has been associated with metastasis. We report here that the overexpression of VEGF(165) in melanoma xenografts promotes an acceleration of tumor growth and an increase in angiogenesis as well as the spontaneous metastasis formation. In addition, VEGF receptors (VEGFR)1, VEGFR2 and neurophilin-1 are expressed in A375 melanoma cells. Forced overexpression of VEGF in these cells induces cell growth and triggers survival activity in serum-starved cultures, by a mechanism dependent on the mitogen-activating protein kinase signaling pathway. Furthermore, these effects are dependent MEK 1/2 activity. Kinase domain region-specific tyrosine kinase inhibitors dramatically reduced DNA synthesis to 20% with respect to the controls, although they did not completely suppress either the p44 or p42-phosphorylated forms of extracellular signal-regulated protein kinase. These inhibitors also provoked a decrease in Akt phosphorylation. We observed a dramatic reduction in survival after treatment with phosphatidylinositol 3'-kinase (PI3K)-specific inhibitor in the presence of specific tyrosinase inhibitors. We suggest that the overproduction of VEGF(165) concomitantly expressed with its receptors favors cell growth and survival of melanoma cells through MAPK and PI3K signaling pathways. These data support the involvement in melanoma growth and survival of a VEGF-dependent internal autocrine loop mechanism, at least in vitro.
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PMID:Overproduction of VEGF concomitantly expressed with its receptors promotes growth and survival of melanoma cells through MAPK and PI3K signaling. 1561 May 28

Betulinic acid (BA), a plant derived triterpenoid, isolated from various sources shows cytotoxicity in cell lines of melanoma, neuroectodermal and malignant brain tumors. Chronic myelogenous leukemia (CML) is characterized by Philadelphia chromosome (Bcr-Abl), a molecular abnormality leading to the intrinsic tyrosine kinase activity that provides growth and survival advantage to the cells. Present study describes the cytotoxicity of BA on human CML cell line K-562, positive for Bcr-Abl. The decrease in the viability of K-562 cells treated with BA at different concentrations and time intervals was assessed using MTT assay. Cell death induced by BA was determined to be apoptotic as measured by FACS analysis of PI stained nuclei, PS externalization by Annexin-V fluorescence and characteristic DNA fragmentation. DiOC6(3) fluorescent probe determined alterations in the mitochondrial membrane potential (MMP). RT-PCR confirmed the expression levels of Bcr-Abl in controls and K-562 cells treated with BA. The rapid loss of MMP of K-562 cells upon treatment with BA shows the direct activation of apoptosis at the level of mitochondria, overcoming the resistance of the high levels of expression of Bcr-Abl.
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PMID:Betulinic acid induces apoptosis in human chronic myelogenous leukemia (CML) cell line K-562 without altering the levels of Bcr-Abl. 1564 17

Dracorhodin perchlorate, an anthocyanin red pigment, induces human melanoma A375-S2 cell death through the apoptotic pathway. Caspase-3, -8, -9, and -10 inhibitors partially reversed the cell death induced by dracorhodin perchlorate. Caspase-3 and -8 were activated, followed by the degradation of caspase-3 substrates, the inhibitor of caspase-activated DNase, and poly-(ADP-ribose) polymerase. Dracorhodin perchlorate upregulated the expression ratio of Bax/Bcl-2 and significantly increased the expression of p53 and p21(WAF1) proteins. The cell death was partially reduced by the mitogen-activated protein kinase c-JUN NH2-terminal protein kinase (JNK MAPK) inhibitor (SP600125) and p38 MAPK inhibitor (SB 203580), while the MEK inhibitor (PD98059) augmented cell death; the drug induced sustained phosphorylation of JNK and p38 MAPK. Moreover, the Fas agonistic antibody CH-11 has a synergistic effect with dracorhodin perchlorate. The phoshatidylinositol 3-kinase (PI3-K) family inhibitor wortmanin and tyrosine kinase inhibitor genistein rescued the viability loss induced by dracohodin perchlorate. Taken together, dracorhodin perchlorate induces apoptosis in A375-S2 cells via accumulation of p53, alters the Bax/Bcl-2 ratio, and activates caspases and p38/JNK MAPKs.
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PMID:Dracorhodin perchlorate induces A375-S2 cell apoptosis via accumulation of p53 and activation of caspases. 1568 74

N-Phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas were found to be a novel class of potent inhibitors for the vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase through synthetic modifications of a lead compound and structure-activity relationship studies. A representative compound 6ab, termed Ki8751, inhibited VEGFR-2 phosphorylation at an IC(50) value of 0.90 nM, and also inhibited the PDGFR family members such as PDGFRalpha and c-Kit at 67 nM and 40 nM, respectively. However, 6ab did not have any inhibitory activity against other kinases such as EGFR, HGFR, InsulinR and others even at 10000 nM. 6ab suppressed the growth of the VEGF-stimulated human umbilical vein endothelial cell (HUVEC) on a nanomolar level. 6ab showed significant antitumor activity against five human tumor xenografts such as GL07 (glioma), St-4 (stomach carcinoma), LC6 (lung carcinoma), DLD-1 (colon carcinoma) and A375 (melanoma) in nude mice and also showed complete tumor growth inhibition with the LC-6 xenograft in nude rats following oral administration once a day for 14 days at 5 mg/kg without any body weight loss.
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PMID:Novel potent orally active selective VEGFR-2 tyrosine kinase inhibitors: synthesis, structure-activity relationships, and antitumor activities of N-phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas. 1574 79

Previous studies indicated that transfection of the platelet integrin alphaIIbbeta3 into human melanoma cells expressing integrin alphavbeta3 promoted their in vivo (but not in vitro) growth and cell survival. To reveal the underlying pathomechanism, we have analyzed the angiogenic phenotype of alphaIIbbeta3 integrin-transduced human melanoma cells expressing integrin alphavbeta3. Upon heterotopic or orthotopic (intracutaneous) injections into SCID mice, the alphaIIbbeta3 integrin-overexpressing clones, ESL, ESH, 19L and 19H, grew more rapidly than the mock transfectant (alphavbeta3 expressing) clone, 3.1P. Morphometry demonstrated an increased intratumoral microvessel density in 19L and 19H tumors compared to 3.1P. Immunocytochemistry and flow cytometry indicated that vascular endothelial growth factor (VEGF) is constitutively expressed in the majority of the cells of both the mock and the alphaIIbbeta3 integrin-transfected clones. However, the mock transfectant clone, 3.1P, did not express basic fibroblast growth factor (bFGF) at protein level (<1%), unlike the alphaIIbbeta3 integrin-transfected clones, 19L and 19H, (33.9 and 84.1%, respectively). Quantitative PCR analysis of 6 related human melanoma clones with various levels of alphaIIbbeta3 integrin expressions revealed a correlation between the alphaIIb protein and bFGF mRNA expressions. Furthermore, cDNA microarray analysis of the 19H cells revealed 12 downregulated and 36 upregulated genes [among them 3 upregulated vasculogenic mimicry-genes (CD34, endothelin receptor B, Prostaglandin I-2 synthase)] when compared to 3.1P cells. The altered bFGF expression may be influenced by integrin-linked signaling, since bbeta3-endonexin is upregulated in alphaIIbbeta3-transfected cells and tyrosine kinase inhibitors downregulate bFGF both at mRNA and protein levels. We propose here that the illegitimate expression of alphaIIbbeta3 integrin in human melanoma cells already expressing alphavbeta3 integrin may alter their in vivo growth properties due to the modulation of their angiogenic phenotype.
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PMID:Parallel expression of alphaIIbbeta3 and alphavbeta3 integrins in human melanoma cells upregulates bFGF expression and promotes their angiogenic phenotype. 1576 67

Imatinib mesylate (IM) is a tyrosine kinase inhibitor, which inhibits phosphorylation of downstream proteins involved in BCR-ABL signal transduction. It has proved beneficial in treating patients with chronic myeloid leukaemia (CML). In addition, IM demonstrates activity against malignant cells expressing c-kit and platelet-derived growth factor receptor (PDGF-R). The activity of IM in the blastic crisis of CML and against various myeloma cell lines suggests that this drug may also target other cellular components. In the light of the important role of telomerase in malignant transformation, we evaluated the effect of IM on telomerase activity (TA) and regulation in various malignant cell lines. Imatinib mesylate caused a dose-dependent inhibition of TA (up to 90% at a concentration of 15 microM IM) in c-kit-expressing SK-N-MC (Ewing sarcoma), SK-MEL-28 (melanoma), RPMI 8226 (myeloma), MCF-7 (breast cancer) and HSC 536/N (Fanconi anaemia) cells as well as in ba/F3 (murine pro-B cells), which do not express c-kit, BCR-ABL or PDGF-R. Imatinib mesylate did not affect the activity of other DNA polymerases. Inhibition of TA was associated with 50% inhibition of proliferation. The inhibition of proliferation was associated with a decrease in the S-phase of the cell cycle and an accumulation of cells in the G2/M phase. No apoptosis was observed. Inhibition of TA was caused mainly by post-translational modifications: dephosphorylation of AKT and, to a smaller extent, by early downregulation of hTERT (the catalytic subunit of the enzyme) transcription. Other steps of telomerase regulation were not affected by IM. This study demonstrates an additional cellular target of IM, not necessarily mediated via known tyrosine kinases, that causes inhibition of TA and cell proliferation.
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PMID:Imatinib mesylate (Gleevec) downregulates telomerase activity and inhibits proliferation in telomerase-expressing cell lines. 1587 Jul 11

We have prepared the map of regional distribution of cervical cancer in Hungary. Serial HPV genotyping of sexual partners provided evidence for the sexually transmitted infections. Molecular epidemiology studies revealed activating c-kit mutation in bilateral testicular cancers. A cost-effective molecular staging method was introduced to the management of breast cancer patients. Genomic profiling identified the gene signature of Herceptin and taxane sensitivity of breast cancer. In colon cancer patients we have determined the mutational spectrum of hMLH1 and hMSH2 genes in Hungary. The prognostic power of SHMT and MTHFR polymorphism was determined in colorectal cancer patients. In head and neck cancer the gene signature of cisplatin sensitivity and the EGFR polymorphism was determined. We have introduced a cost-effective in vitro assay to determine the drug resistance of pediatric leukemias. The prognostic power of N-myc genotyping was determined in neuroblastoma patients. A phase I trial for gene therapy of brain cancer was started by using a GM-CSF adenoviral vector system. Using global genomic approaches the gene signature of malignant melanoma and its metastatic disease was determined. We have found that Ca-channel blockers and EGFR tyrosine kinase inhibitors are effective in preclinical human melanoma models in breaking the apoptosis resistance of this tumor.
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PMID:[Activity of the National Oncology R&D Consortium in 2004]. 1590 26

Assessment of tumour vascularity may characterize malignancy as well as predict responsiveness to anti-angiogenic therapy. Non-invasive measurement of tumour perfusion and blood vessel permeability assessed as the transfer constant, K(trans), can be provided by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Using the orthotopic murine tumour model B16/BL6 melanoma, the small contrast agent GdDOTA (DOTAREM(R); Guerbet, Paris) was applied to assess the vascular transfer constant, K(trans), and interstitial leakage space, whereas intravascular iron oxide nanoparticles (Endorem(R); Guerbet, Paris) were used to detect relative tumour blood volume (rTBV), and in one experiment blood flow index (BFI). No correlations were observed between these four parameters (r(2) always <0.05). The B16/BL6 primary tumour and lymph-node cervical (neck) metastases produced high levels of the permeability/growth factor, VEGF. To probe the model, the novel VEGF receptor (VEGF-R) tyrosine kinase inhibitor, PTK787/ZK222584 (PTK/ZK) was tested for anti-tumour efficacy and its effects on DCE-MRI measured parameters of tumour vascularity. Data from the non-invasive measure of tumour vascularity were compared with a histological measurement of vasculature using the DNA-staining dye H33342. PTK/ZK inhibited growth of the primary and, particularly, cervical tumour metastases following chronic treatment for 2 weeks (50 or 100 mg/kg daily) of 1-week-old tumours, or with 1 week of treatment against more established (2-week-old) tumours. After chronic treatment with PTK/ZK, DCE-MRI detected significant decreases in K(trans) and interstitial leakage space, but not rTBV of both primary tumours and cervical metastases. Histological data at this time-point showed a significant decrease in blood vessel density of the cervical metastases but not the primary tumours. However, in the cervical metastases, the mean blood vessel width was increased by 38%, suggesting overall no marked change in blood volume. After acute (2-4 day) treatment, DCE-MRI of the cervical metastases demonstrated a significant decrease in K(trans) and interstitial leakage space and also in the initial area under the enhancement curve for GdDOTA (IAUC), but no change in the rTBV or BFI. Thus, significant changes could be detected in the DCE-MRI measurement of tumour uptake of a small contrast agent prior to changes in tumour size, which suggests that DCE-MRI could be applied in the clinic as a rapid and sensitive biomarker for the effects of VEGF-R inhibition on tumour blood vessel permeability and thus may provide an early marker for eventual tumour response.
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PMID:PTK787/ZK222584, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor, reduces uptake of the contrast agent GdDOTA by murine orthotopic B16/BL6 melanoma tumours and inhibits their growth in vivo. 1591 78

Activating mutations in the BRAF kinase have been reported in a large number of cases of malignant melanoma. This suggests that therapy with specific RAF kinase inhibitors may find use in treating this disease. If the response to RAF kinase inhibition is dependent on the presence of an activated BRAF protein, it will be necessary to evaluate cases of malignant melanoma for the presence or absence of BRAF mutations. High-resolution amplicon melting analysis is able to detect single base-pair changes in DNA isolated from paraffin-embedded tissue sections and obviates the need for direct DNA sequencing. Results can be available within 48 hours. In this report, we used high-resolution amplicon melting analysis to evaluate 90 cases of malignant melanoma for BRAF mutations. Of these 90 cases, 74 were metastatic melanomas, 12 were primary cutaneous melanomas, and 4 were in situ melanomas. BRAF activation mutations were found in 43 cases (48%). Forty-one of these mutations were in exon 15. The mutations in exon 15 included V600E (34 cases), V600K (6 cases), and V600R (1 case). Two activating mutations were found in exon 11, G469V and G469R. The presence or absence of a BRAF mutation in the junctional component of an invasive melanoma was maintained in the invasive component. We also evaluated these 90 cases, as well as an additional 10 cases (total of 100) for the expression of c-kit. The majority of invasive and metastatic malignant melanomas did not express c-kit, although all in situ lesions and the junctional components of invasive lesions were strongly c-kit positive. Surprisingly, 2 cases of metastatic malignant melanoma (2%) showed strong and diffuse c-kit expression and contained a c-kit-activating mutation, L576P, as detected by high-resolution amplicon melting analysis and confirmed by direct DNA sequencing. These 2 c-kit mutation-positive cases did not contain BRAF mutations. The presence of a c-kit-activating mutation in metastatic malignant melanoma suggests that a small number of melanomas may progress by a somatic mutation of the c-kit gene. The presence of BRAF- and c-kit-activating mutations in malignant melanoma suggests new approaches to treating this disease involving specific tyrosine kinase inhibitors may prove worthwhile and that mutation analysis by high-resolution melting analysis might help guide therapy.
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PMID:Human malignant melanoma: detection of BRAF- and c-kit-activating mutations by high-resolution amplicon melting analysis. 1594 15

The c-kit gene encodes a transmembrane receptor (KIT) with tyrosine kinase activity which is a specific target for anti-cancer therapy. We investigated KIT expression in a group of patients with early-stage malignant melanoma. Primary tumour specimens obtained from 261 radically resected patients with stage I and II malignant melanoma were examined for KIT expression. Formalin-fixed, paraffin embedded tissues were stained with the polyclonal rabbit anti-human anti-KIT antibody (Dako Cytomation Inc., Carpenteria, California, USA). Patients were classified into four groups according to the level of expression (0%, <30%, 30-60% and >60%). Univariate and multivariate analyses examining the impact of KIT expression, Breslow thickness, Clark level and microscopic ulceration on disease-free survival were performed. Within the population of 261 patients with early-stage melanoma with 62 recurrences during a follow-up of 64 months, KIT expression was found in 144 cases (55%). KIT was expressed in more than 60% of cells in 20 patients (8%), in 30-60% of cells in 64 patients (24%) and in less than 30% of cells in 60 patients (23%). KIT expression was not found in 117 patients (45%). In univariate analyses, the influence of KIT expression on disease-free survival was not proven (P=0.4956; log-rank test). Increasing Breslow thickness, a higher Clark level, the presence of microscopic ulceration and a higher stage were significantly associated with a shorter disease-free survival (P<0.0001; log-rank test in all cases). In multivariate analysis, Breslow thickness, stage and KIT expression were significant negative prognostic factors for a shorter disease-free survival (P<0.0001, P=0.0028, P=0.0488, respectively; stepwise Cox regression model). It can be concluded that KIT is expressed in more than one-half of early-stage malignant melanoma. KIT may serve as an additive prognostic factor to Breslow thickness and stage within the tested population. The therapeutic impact of KIT expression in malignant melanoma is uncertain. Results of ongoing pilot phase II studies may validate the efficacy of imatinib mesylate in malignant melanoma expressing KIT.
Melanoma Res 2005 Aug
PMID:KIT receptor is expressed in more than 50% of early-stage malignant melanoma: a retrospective study of 261 patients. 1603 2

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