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

---

Query: UMLS:C0027627 (metastases)
103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 37-year-old man was diagnosed with metastatic dermatofibrosarcoma. Dermatofibrosarcoma protuberans is a rare skin tumour with a strong tendency for infiltrative growth, resulting in a high rate of local recurrences; metastatic disease develops in approximately 5% of patients, especially in the lungs. On the basis of some recent publications about the use of imatinib in patients with dermatofibrosarcoma, the patient was prescribed this drug. The treatment resulted in a partial response. Imatinib is the first registered selective tyrosine-kinase inhibitor for treatment of chronic myeloid leukaemia. The inhibition of tyrosine kinase interrupts the proliferative signal transduction.
...
PMID:[Good response to treatment with the selective tyrosine-kinase inhibitor imatinib in a patient with metastatic dermatofibrosarcoma protuberans]. 1460 47

High expression of epidermal growth factor receptor (EGFR) is frequently observed in many solid tumor types including oral squamous cell carcinomas (OSCC). This study investigated whether treatment with gefitinib ('Iressa'), an EGFR-tyrosine kinase inhibitor, would inhibit the metastatic spread in OSCC cells. This was evaluated using orthotopic xenografts of highly metastatic OSCC. Metastasis was observed in six of 13 gefitinib treated animals (46.2%), compared with all of 12 control animals (100%). After exposure to gefitinib, OSCC cells showed a marked reduction in cell adhesion ability to fibronectin and in the expression of integrin alpha3, alphav, beta1, beta4, beta5 and beta6.
...
PMID:Gefitinib ('Iressa'), an epidermal growth factor receptor tyrosine kinase inhibitor, mediates the inhibition of lymph node metastasis in oral cancer cells. 1460 28

Signaling through vascular endothelial growth factor (VEGF) receptors (VEGFRs) is a key pathway initiating endothelial cell proliferation and migration resulting in angiogenesis, a requirement for human tumor growth and metastasis. Abrogation of signaling through VEGFR by a variety of approaches has been demonstrated to inhibit angiogenesis and tumor growth. Small molecule inhibitors of VEGFR tyrosine kinase have been shown to inhibit angiogenesis, inhibit tumor growth, and prevent metastases. Our goal was to discover and characterize an p.o. active VEGFR-2 small molecule inhibitor. A novel isothiazole, CP-547,632, was identified as a potent inhibitor of the VEGFR-2 and basic fibroblast growth factor (FGF) kinases (IC(50) = 11 and 9 nM, respectively). It is selective relative to epidermal growth factor receptor, platelet-derived growth factor beta, and other related TKs. It also inhibits VEGF-stimulated autophosphorylation of VEGFR-2 in a whole cell assay with an IC(50) value of 6 nM. After oral administration of CP-547,632 to mice bearing NIH3T3/H-ras tumors, VEGFR-2 phosphorylation in tumors was inhibited in a dose-dependent fashion (EC(50) = 590 ng/ml). These plasma concentrations correlated well with the observed concentrations of the compound necessary to inhibit VEGF-induced corneal angiogenesis in BALB/c mice. A sponge angiogenesis assay was used to directly compare the inhibitory activities of CP-547,632 against FGF receptor 2 or VEGFR-2; this compound potently inhibits both basic FGF and VEGF-induced angiogenesis in vivo. The antitumor efficacy of this agent was evaluated after once daily p.o. administration to athymic mice bearing human xenografts and resulted in as much as 85% tumor growth inhibition. CP-547,632 is a well-tolerated, orally-bioavailable inhibitor presently under clinical investigation for the treatment of human malignancies.
...
PMID:Pharmacological characterization of CP-547,632, a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for cancer therapy. 1461 27

Many malignant tumors including non-small cell lung cancer (NSCLC) express or over-express EGFR that have shown correlations with rapid growth, metastases, resistance to conventional chemotherapy or radiotherapy, and poor prognosis. Gefitinib is a potent and selective inhibitor of EGFR tyrosine kinase (EGFRTK). Gefitinib specifically inhibited EGF-stimulated cell proliferation in vitro and it also exhibited a broad anti-tumor spectrum against NSCLC, prostate, colorectal, and ovarian cancers in vivo. Gefitinib showed dose-dependent and reversible reduction of c-fos mRNA level and decreased Ki67 significantly in tumors in vivo. In in vitro studies, gefitinib arrested the cell cycle at G1 phase by inducing intrinsic cyclin-dependent kinase (cdk) inhibitors and following inhibition of cdk2. Apoptosis was also seen in gefitinib-treated tumor cells and skin biopsy samples from clinical study. Gefitinib inhibited VEGF production in tumor cells through inhibition of EGFR signaling, leading to suppression of angiogenesis. In clinical studies, gefitinib demonstrated therapeutic benefit in patients who failed conventional chemotherapy. No correlation has been established between the anti-tumor activity of gefitinib and EGFR expression level, whilst sensitivity factors to gefitinib are yet to be elucidated. Identification of sensitivity factors will be a key for effective use of EGFRTK inhibitors including gefitinib for cancer treatment.
...
PMID:EGFR tyrosine kinase inhibitor "gefitinib (Iressa)" for cancer therapy. 1463 3

Even when diagnosed at the earliest stages, non-small-cell lung cancer (NSCLC) has often begun to metastasize, leading to frequent systemic relapses and a poor prognosis. There is an urgent need for effective adjuvant systemic therapy in conjunction with surgery to reverse or control further growth of micrometastases in early-stage NSCLC. Several approaches have been investigated in the search for such a therapy, including various chemotherapies, applied preoperatively or postoperatively, chemopreventive agents, and molecular-targeted agents. This article presents an overview of clinical trials for these adjunctive therapies, including completed trials and trials whose results are anticipated. Although standard postoperative chemotherapy has been found to offer little benefit, likely because of the acquisition of resistance in advanced tumors, some clinical trials with neoadjuvant or alternative chemotherapies have produced encouraging results. Targeted agents such as the epidermal growth factor receptor/tyrosine kinase inhibitor gefitinib have shown early promise for effective disease control. A combination of these new approaches and standard therapy for NSCLC may improve long-term survival in patients with lung cancer
...
PMID:Adjuvant systemic therapies in early-stage non-small-cell lung cancer. 1464 92

Cholangiocarcinoma (CCA) is a lethal disease, afflicting many thousands the world over. Human CCA develops through a multi-step progression model, preceded by the onset of dysplasia in the cholangiolar ductal epithelium. An animal model of multi-step carcinogenesis in the biliary tree will enable the study of genetic changes in human CCA, and provide an avenue for chemoprevention strategies. We describe an oral thioacetamide (TAA)-induced model of rat CCA that recapitulates the histologic progression of human CCA. Male Sprague-Dawley (SD) rats (n = 170), weighing 350 +/- 20 g, were used in this study. Drinking water with TAA 300 mg/l was administered orally, and the liver was harvested and examined histologically at weekly intervals, beginning at 5 weeks after initiation of TAA. Harvested tissues were formalin-fixed and paraffin embedded for morphologic and immunohistochemical studies. Multifocal bile ductular proliferation with intestinal metaplasia (presence of goblet cells) and increasing histologic atypia (biliary dysplasia) was observed by the 9th week of TAA administration. Biliary cytokeratin (CK19)-expressing invasive intestinal-type CCA with stromal desmoplasia was evident at the 16th week, and by the 22nd week, the yield rate for CCAs had increased to 100%. Invasive CCAs preceded the development of hepatic cirrhosis by at least 4 weeks; the earliest incidence of hepatic fibrosis was observed beginning at 20 weeks post-TAA administration. The progression from normal cholangioles to biliary dysplasia to invasive CCA was accompanied by up-regulation of the proto-oncogenes c-met and c-erbB-2, tyrosine kinase receptors over-expressed in human CCAs. The study was terminated at 6 months, at which time no systemic metastases or deaths were observed. Oral administration of TAA in drinking water to male SD rats provides a reproducible animal model for development of CCA with a high yield rate. In particular, the presence of biliary dysplasia beginning at the 9th week, which progresses to invasive CCA, mimics the multi-step model of human CCA. The TAA rat model may serve as a powerful pre-clinical platform for therapeutic and chemoprevention strategies for human CCA.
...
PMID:Thioacetamide-induced intestinal-type cholangiocarcinoma in rat: an animal model recapitulating the multi-stage progression of human cholangiocarcinoma. 1465 42

A novel orthotopic metastatic model of mouse prostate cancer was developed using MHC-negative TRAMP-C1P3 (transgenic adenocarcinoma of mouse prostate) cells derived by serial passage of the parental TRAMP-C1 line in mouse prostate glands. TRAMP-C1P3 cells grew efficiently in mouse prostate glands and reproducibly metastasized to draining lymph nodes. Using this model, we show that Fms-like tyrosine kinase-3 ligand (flt3-L) dramatically inhibited growth of preexisting orthotopic TRAMP-C1P3 tumors and the development of metastatic disease. Mice remained in remission for several months following termination of flt3-L treatment but eventually relapsed and died of progressive disease. flt3-ligand treatment induced a pronounced mixed inflammatory cell infiltrate that consisted of CD8alpha-CD4- dendritic cells (CD11c+), macrophages, granulocytes (Gr-1+) and to a lesser extent T cells (CD4+ and CD8+). Dendritic cells isolated from TRAMP-C1P3 tumors were phenotypically immature (CD11c+ B7.2-I-A-CD40-), and this phenotype was also predominant in peripheral organs of mice treated with flt3-L alone or in combination with the DC maturation factor, CD40-L. Diminished expression of TCR-beta, CD3-epsilon, and CD3-zeta was also observed on intratumoral T cells, although these signaling proteins were reexpressed following in vitro culture with IL-2. The TCR/CD3 complex remained intact on peripheral T cells except in mice treated with flt3-L where CD3-zeta loss was observed. In contrast to alphabeta-T cells, tumor-infiltrating gammadelta-T cells maintained expression of their antigen receptors but not CD3epsilon. Thus, TRAMP-C1P3 tumors quickly establish a microenvironment that profoundly diminishes expression of molecules critical for normal dendritic cell and T cell function, thus limiting the efficacy of flt3-L and CD40-L immunotherapy. Overall, these data suggest that long-term cures of established MHC-negative tumors may not be achieved until therapeutic interventions are engineered to overcome this immunosuppressive microenvironment.
...
PMID:Prostate tumor microenvironment alters immune cells and prevents long-term survival in an orthotopic mouse model following flt3-ligand/CD40-ligand immunotherapy. 1467 30

To systematically identify genes related to invasion a three-dimensional multicellular matrix invasion assay was used to classify human tumor cell lines as stromal invasion positive or stromal invasion negative. Cells from two of the primary cell types of the stromal compartment [endothelial cells (HMVEC) and myofibroblasts (HDF)] were assayed for invasion into tumor cell clusters (breast carcinoma, ovarian carcinoma, prostate carcinoma, lung carcinoma, and melanoma). Four tumor cell lines (MDA-MB231, SKOV-3, A375, and MEL624) scored invasion positive, and four tumor cell lines (LNCaP, DU145, PC3, and A549) scored invasion negative. Serial analysis of gene expression (SAGE) libraries generated from the tumor cell lines were analyzed by GeneSpring Hierarchical clustering, t test, and chi(2) test. Clusters emerged that reflected the behavior in the cell culture assay. Of the 47 most highly differentially expressed genes, 30 were selected for confirmation by real-time PCR, and 9 had good correlation with normalized serial analysis of gene expression tag counts. The strongest correlations were for bone marrow stromal antigen 2, stathmin-like 3, tumor necrosis factor receptor superfamily member 5, and hepatocyte growth factor tyrosine kinase substrate. In situ hybridization of metastatic and nonmetastatic ovarian cancer demonstrated selective expression of bone marrow stromal antigen 2 and tumor necrosis factor receptor superfamily member 5 in the metastatic disease. This combination approach appears to be a powerful tool for identifying genes that may be useful as diagnostic markers and/or as therapeutic targets for invasive solid tumors.
...
PMID:Identification of genes expressed in malignant cells that promote invasion. 1469 11

Gastrointestinal stromal tumors (GISTs) are rare tumors of the wall of the stomach and small bowel, and also occasionally arise in the mesentery, omentum, or retroperitoneum. The incidence of GIST in the United States is approximately 500 to 750 patients per 100,000 people. GISTs often present late in their clinical course unless they are the cause of gastrointestinal bleeding or perforation. Surgical resection is the standard of care for primary GIST. However, there is a high risk of recurrence in the peritoneum and liver. For metastatic GIST, imatinib mesylate is the standard of care. Two phase III studies presented in 2003 in abstract form show slightly different results. In the US study, 400 mg/d was found to be equivalent to 800 mg/d with respect to response, progression-free survival, and overall survival at 12 months. In the European/Australasian study, the response rate was the same with either dosage, but progression-free survival was better with 800 mg/d compared with 400 mg/d. Overall survival data for the latter study were too immature for analysis as of May 2003. Adjuvant or neoadjuvant therapy with imatinib is the topic of at least three studies through the American College of Surgeons Oncology Group and Radiation Therapy Oncology Group and the American College of Radiology Imaging Network. Every effort to enroll eligible patients on these studies should be made. New treatments for metastatic disease under investigation include a tyrosine kinase inhibitor with an expanded panel of targets compared with imatinib (SU011248), and the addition of a mammalian target of rapamycin (mTOR) inhibitor and the rapamycin derivative RAD001 to imatinib. Given the finding of a specific molecular defect to exploit, GISTs have gone from an orphan disease to a proving ground for tyrosine kinase-targeted therapy.
...
PMID:Gastrointestinal Stromal Tumors Respond to Tyrosine Kinase-targeted Therapy. 1472 34

Despite new therapies and several treatment options, metastatic breast cancer (MBC) remains incurable. One reason for the low median survival rate may be intense cross-talk between growth factor receptors such as the epidermal growth factor receptor (EGFR/HER1) and the HER2 growth factor receptor. This report describes the case history of a patient with MBC whose disease had progressed despite surgery, radiotherapy and four different chemotherapy regimens, including trastuzumab (a monoclonal antibody that specifically blocks HER2) combined with docetaxel. However, treatment with 500 mg/day gefitinib ('Iressa', ZD1839), an EGFR tyrosine kinase inhibitor, and trastuzumab (2 mg/kg/week) caused a rapid and sustained regression of breast cancer metastases in skin and lymph nodes. Thus, for patients with MBC whose tumors co-express EGFR and HER2, gefitinib in combination with trastuzumab may prevent receptor cross-talk, improving the outcome of MBC.
...
PMID:Induction of remission in a patient with metastatic breast cancer refractory to trastuzumab and chemotherapy following treatment with gefitinib ('Iressa', ZD1839). 1501 56


<< Previous 1 2 3 4 5 6 7 8 9 10

---