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: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant mesothelioma (MM) is a tumor of the pleura for which there is no satisfactory treatment. It is an almost universally fatal disease, regardless of the stage of the tumor at the time of diagnosis. Current treatment modalities include surgery, chemotherapy, and radiation therapy, although in some series none of these modalities is superior to no treatment at all. Because of the dismal prognosis for patients with MM, new modes of treatment are desperately needed. A promising area of research into the treatment of various malignancies is gene therapy. Recent studies have demonstrated the utility of exposing tumor cells to cells transduced to express the Herpes simplex virus gene for thymidine kinase (HSV-TK). By virtue of their expression of HSV-TK, the transduced cells are rendered susceptible to the antiviral drug, ganciclovir (GCV). Nearby untransduced tumor cells are killed by a so-called bystander effect. We are describing a Phase I clinical gene therapy trial for MM, which we are presently conducting at the Louisiana State University Medical Center of New Orleans. The purpose is to study the safety and to determine the maximal tolerated dose of an HSV-TK-transduced ovarian cancer cell line (PA1-STK cells) that is infused into the pleural cavities of patients. This infusion is followed by systemic administration of GCV. The hope is that administration of GCV will result in killing of both the transduced ovarian cancer cells as well as the nearby malignant cells.
...
PMID:Gene therapy for malignant mesothelioma: a novel approach for an incurable cancer with increased incidence in Louisiana. 961 71

Malignant mesothelioma (MM) is a thoracic malignancy that is increasing in incidence. Since it is uniformly fatal and kills by local spread, investigators have proposed that MM is a good target for novel treatment approaches, such as gene therapy. We hypothesized that delivery of the HSV-tk gene, using gene-modified tumor cells (PA-1-STK cells), would result in an antitumor effect after treatment with ganciclovir. In in vitro mixing experiments, we found that PA-1-STK cells killed both mouse and human mesothelioma cells in a dose-dependent manner. Moreover, we found that PA-1-STK cells also prolonged survival of mice with MM when the percentage of total tumor cells was high (70%), but observed no survival benefit when the percentage of PA-1-STK cells was low (30%). These data support the rationale for a cell-based gene therapy approach to MM.
...
PMID:Antitumor activity with the HSV-tk-gene-modified cell line PA-1-STK in malignant mesothelioma. 969 7

Malignant mesothelioma is a tumor of the pleura for which there is no satisfactory treatment. It is almost universally fatal, regardless of the stage of the tumor at the time of diagnosis. Current treatment modalities include surgery, chemotherapy, and radiation therapy, although in some series none of these modalities is superior to no treatment at all. Because of the dismal prognosis for patients with malignant mesothelioma, a new mode of treatment is desperately needed. A promising area of research into the treatment of various malignancies is gene therapy. Recent studies have demonstrated the utility of exposing tumor cells to cells transduced to express the Herpes simplex virus gene for thymidine kinase (HSV-tk). By virtue of their expression of HSV-tk, the transduced cells are rendered susceptible to the antiviral drug, ganciclovir (GCV). and nearby tumor cells are killed by a phenomenon termed the bystander effect. In this protocol we propose a Phase I trial to study the safety and determine the maximal tolerated dose of an HSV-tk-transduced ovarian cancer cell line (PA1-STK cells) infused into the pleural cavities of patients with malignant pleural mesothelioma, followed by systemic administration of ganciclovir. The hope is that administration of ganciclovir will result in killing of the HSV-tk transduced ovarian cancer cells as well as the nearby malignant mesothelioma cells. This is a standard dose-escalation protocol.
...
PMID:The treatment of malignant mesothelioma with a gene modified cancer cell line: a phase I study. 985 30

Overexpression of KIT protein (CD117), the product of the c-kit gene, has been shown to have important prognostic and therapeutic implications for a number of malignant neoplasms. Previous studies have shown conflicting results regarding the expression of c-kit in malignant mesothelioma. To determine whether malignant mesothelioma expresses KIT, immunohistochemistry and RT-PCR were used to analyze archived tissue from 37 cases of mesothelioma. Although a subset of mesotheliomas demonstrated specific staining with the DAKO anti-KIT antibody, in each case staining was nuclear. We could not detect c-kit mRNA by a sensitive RT-PCR assay, even in cases with strong nuclear staining. Furthermore, a second anti-KIT antibody (Cell-Marque) only demonstrated staining in a single mesothelioma case and in none of the cases that demonstrated nuclear staining. We conclude that immunoreactivity for KIT in mesothelioma does not represent expression of the c-kit gene and may represent antibody cross-reaction with nuclear proteins. Our results raise doubt about previously reported expression of KIT in mesothelioma and consequently, the applicability of therapeutic agents that target the kinase activity of KIT.
...
PMID:c-Kit is not expressed in malignant mesothelioma. 1526 10

Malignant mesothelioma (MM) remains the most lethal pleural, peritoneal and pericardial cancer. Here, we characterize the effects of nonsteroidal anti-inflammatory agents (NSAIDs) on in vitro and in vivo experimental MM models. Unlike primary normal mesothelial cells, the selective cyclooxygenase (COX)-2 inhibitor celecoxib reduced the in vitro proliferation of several MM cells derived from previously untreated MM patients. Moreover, celecoxib significantly inhibited MM cell colony formation in soft agarose (63-78% at 5 x 10(-5) M; p < or = 0.05) and it elicited remarkable antitumor activity, leading to long-term survival in >37% of nude mice bearing intraperitoneal MM. Celecoxib was more efficient in inhibiting MM cell growth than acetylsalicylic acid (10(-6) M-10(-2) M), indometacin (10(-6) M-10(-2) M) and the COX-2 inhibitor NS-398 (10(-6) M-10(-4) M). Efficacy of these different compounds was not related to the amount of COX-2 protein levels present on MM cells. Celecoxib, in a dose- and time-dependent manner, induced MM cell apoptosis, which involved decreased Akt phosphorylation, loss of Bcl-2 and Survivin protein expression and caspase-3 activation. Furthermore, vascular endothelial growth factor (VEGF), an MM autocrine growth factor and Akt inducer, rescued celecoxib-induced apoptosis and Akt dephosphorylation. When the VEGF receptor (KDR/Flk-1) inhibitor, SU-1498, was used in combination with celecoxib, IC50 of celecoxib in vitro was reduced up to 65%. These data demonstrate that celecoxib may have antitumor properties in MM and provide a rationale for the therapeutic use of celecoxib in combination with a selective VEGF inhibitor.
...
PMID:Preclinical evaluation of the nonsteroidal anti-inflammatory agent celecoxib on malignant mesothelioma chemoprevention. 1496 68

Heparanase is an endoglycosidase that degrades heparan sulfate (HS) in the extracellular matrix (ECM) and cell surfaces, and fulfills a significant role in cancer metastasis and angiogenesis. We evaluated the expression of heparanase and its possible association with the expression of angiogenic molecules in malignant mesothelioma (MM), and analyzed whether expression of these proteins is site-related (pleural vs peritoneal MM, solid lesions vs effusions). Sections from 80 MM (56 biopsies, 24 effusions) were analyzed for heparanase protein expression using immunohistochemistry (IHC). Sixty MM were of pleural origin, and 20 were peritoneal. Effusion specimens consisted of 6 peritoneal and 18 pleural effusions, while biopsies consisted of 14 peritoneal and 42 pleural lesions. Fifty-four specimens were additionally evaluated for expression of basic fibroblast growth factor (bFGF), interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) proteins using IHC. Microvessel density (MVD) was studied in 28 biopsies using an anti-CD31 antibody. mRNA expression of heparanase (HPSE-1), VEGF and the VEGF receptor KDR was analyzed in 23 effusions using RT-PCR. Heparanase protein expression was seen in 69/80 (86%) tumors. Of these, 35 showed combined membrane and cytoplasmic expression, 30 cytoplasmic expression, and four exclusively membrane expression. Both total (P = 0.001) and cytoplasmic (P = 0.002) expression was significantly higher in solid tumors compared to effusions. Protein expression of VEGF, IL-8 and bFGF was seen in 21/54 (39%), 22/54 (41%) and 44/54 (81%) specimens, respectively. Protein expression of bFGF was significantly higher in solid tumors (P < 0.001) and correlated with heparanase expression (P = 0.005). HPSE-1 and VEGF mRNA expression was detected in all 23 effusions using RT-PCR, while KDR mRNA was found in 12/23 MM. KDR mRNA expression correlated with that of both HPSE-1 (P = 0.005) and VEGF (P = 0.001). Our results document frequent expression of heparanase in MM, in agreement with the biological aggressiveness of this tumor. The co-expression of heparanase with bFGF is in agreement with the role of the former in releasing bFGF from the ECM. The concomitant reduction in protein expression of both molecules in effusions as compared to solid tumors, supports the hypothesis of a reduced need for pro-angiogenic stimuli in effusions, and may aid in defining tumor progression in this setting.
...
PMID:Heparanase and basic fibroblast growth factor are co-expressed in malignant mesothelioma. 1567 72

Asbestos has been recognized in Egypt since a long time as ancient Egyptians were using it in mummification. Mesothelioma in Egypt is mainly attributed to environmental origin with a high incidence of women and young adults affected. The incidence of mesothelioma is rising in Egypt. Epidemiological data for 635 malignant mesothelioma (MM) patients over 4 years in the third Millennium were collected from the National Cancer Institute (NCI), Cairo University and Abbassia Chest hospital. This number is more than four times the number diagnosed in the previous 11 years at NCI. A clinicopathological study was done for 100 malignant pleural mesothelioma (MPM) patients and showed that asbestos exposure and SV40 positivity were evident in 67% and 60% of cases, respectively. The median survival was 14.3 months and the 1 and 2 year survival rates were 60% and 27%, respectively. Evaluation of p53 and pRb immunohistochemically showed that pRb alteration was related to poor survival. Other biological prognostic factors such as EGFR, HER-2, glutathione S transferase (GST) and MDR were evaluated in 50 cases. Overexpression of EGFR was correlated with lack of clinical benefit and poor survival. GST potentiated the effect of EGFR on survival. The use of EGFR inhibitors may have a role in the treatment of MM. Asbestos in Cairo is a silent killer and measures toward eliminating it entirely or at least strictly controlling human contact with this dangerous carcinogen have to be taken in order to combat the coming epidemic of mesothelioma in Egypt.
...
PMID:Epidemic of mesothelioma in Egypt. 1595 Jul 94

Malignant mesothelioma remains a highly lethal cancer. Recent advances in both surgical and medical therapy have improved survival, but the treatments remain toxic and selection of appropriate patients for these therapies is difficult. Research into the molecular pathways involved in the development of mesothelioma should yield information that will guide therapeutic decisions in the near future. In particular, expression of EGFR and VEGF receptor hold promise to alter standards of patient care in the next few years. Alterations in cell cycle control proteins such as p16, p21, and p27 also offer information on prognosis and represent potential targets for therapy.
...
PMID:Molecular prognostic markers in malignant mesothelioma. 1595 Aug 2

Tumorigenesis is associated with the activation of mitogenic signal transduction pathways. The expression of activated extracellular signal-regulated kinase (p-ERK) may play an important role in cell proliferation of malignant mesothelioma (MM). We compare the expression of p-ERK in 50 biopsy specimens of MM, non-small-cell lung cancer (NSCLC), and normal lung tissue. We hypothesized that phosphorylated extracellular signal-regulated kinase is increased in MM. We stained the sections by immunohistochemistry for activated ERK-1 and -2 and performed the quantification of the stained nuclei. Quantitative analysis of p-ERK showed a high percentage score in MM (30.3 +/- 4.6%) as compared with NSCLC (12.2 +/- 2.1%) (p<0.01) and control lung tissue (6.4 +/- 1.3%) (p=0.0002). Furthermore, p-ERK was found significantly higher in poorly differentiated NSCLC (17.7 +/- 3.1%) as compared with well-differentiated NSCLC (5.4 +/- 1.2%) (p<0.01). Our data show that the nuclear quantification of p-ERK is significantly increased in MM and poorly differentiated NSCLC in comparison to well-differentiated NSCLC and normal lung tissue. These results corroborate previous experimental studies that suggest a critical role of p-ERK in cell proliferation of malignant disease and may represent new targets for therapeutic agents.
...
PMID:Phosphorylated extracellular signal-regulated kinases are significantly increased in malignant mesothelioma. 1651 79

Pleural malignant mesothelioma (MM) usually presents with chest pain, pleural effusion, or cough in middle-aged and elderly individuals with a history of asbestos exposure, but may rarely present at unusual metastatic sites. The luminal gastrointestinal (GI) tract is only rarely involved in patients with wide-spread disease at autopsy. Encountering MM in endoscopic GI biopsies is an exceptionally rare event in surgical pathology practice and may therefore pose great diagnostic challenges if not considered, in particular if the clinical history is not informative or the GI symptoms are the presenting signs of the disease. To our knowledge, only three cases of epithelioid mesothelioma (EM) involving the luminal GI tract (intestine) have been reported so far, but no case of sarcomatoid MM (SM) involving the GI mucosa has been described. We herein present the first two cases of MM (one each of EM and SM) of the pleura, presenting in endoscopic gastric biopsies as small polypoid lesions and poorly healing ulcers 30 and 35 months after the initial diagnosis of pleural MM, respectively. The major differential diagnoses encompass primary or metastatic adenocarcinoma in case one and cytokeratin-positive (KIT negative!) GI stromal tumors (GISTs) and sarcomatoid carcinoma in case two, as well as other rare entities.
...
PMID:Epithelioid and sarcomatoid malignant pleural mesothelioma in endoscopic gastric biopsies: a diagnostic pitfall. 1681 45


1 2 3 4 5 Next >>

---