UMLS:C1140680 - FACTA Search

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Query: UMLS:C1140680 (ovarian cancer)
28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of luteinizing hormone-releasing hormone (LHRH) and its receptors has been demonstrated in a number of human malignant tumors, including cancers of the breast, ovary, endometrium and prostate. These findings suggest the presence of an autocrine regulatory system based on LHRH. Recent studies in our laboratory have demonstrated that the function of LHRH produced by ovarian cancer cells is the inhibition of their proliferation. Dose-dependent antiproliferative effects of LHRH-agonists have been observed by several laboratories in cell lines derived from the above cancers. Interestingly, also LHRH-antagonists have marked antiproliferative activity in most of the ovarian, breast and endometrial cancer cell lines tested so far, indicating that the dichotomy of LHRH-agonists/LHRH-antagonists is not valid for the LHRH-system in cancer cells. In addition, our data suggest that the classical LHRH receptor signal transduction mechanisms known from the pituitary (phospholipase-C, protein kinase C, adenylyl cyclase) are not involved in the mediation of LHRH effects in cancer cells. Data obtained by several groups, including ours, rather suggest that LHRH analogs interfere with the signal transduction of growth-factor receptors and related oncogene products associated with tyrosine-kinase activity. The mechanism of action is probably an LHRH-induced activation of a phosphotyrosine phosphatase, counteracting the effects of receptor associated tyrosine kinase. In our hands, LHRH analogs virtually blocked the EGF-induced MAP-kinase activity of ovarian and endometrial cancer cells. The pharmacological exploitation of this mechanism might provide promising new therapies for these cancers.
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PMID:Effects of LHRH-analogues on mitogenic signal transduction in cancer cells. 969 74

Tumor-associated lymphocytes (TALs) freshly isolated from patients with cancer usually manifest reduced proliferative and cytolytic functions. To determine whether alterations in signal transduction contribute to functional impairments seen in TALs, we purified populations of T and natural killer (NK) cells by negative selection from ascites of seven patients with ovarian carcinoma. The average purity was 84 +/- 5% for CD3(+) TALs and 77 +/- 10% for CD3(-)CD56(+)CD16(+) TALs. Expression of several signal transduction molecules, including the CD3-epsilon, CD3-zeta, and FcepsilonRI-gamma chains, p56(lck) protein tyrosine kinase, and phospholipase C-gamma1, was studied in these cells using Western blotting. A marked decrease in expression of zeta and FcepsilonRI-gamma associated with CD3 or FcgammaRIIIA was observed in T or NK cells obtained from TALs, as compared to T or NK cells purified from normal peripheral blood. Expression of CD3-epsilon, as assessed using flow cytometry, Western blotting, or ELISA was also reduced in purified TAL-T cells relative to that in normal peripheral blood T cells. Surface expression of CD3 on T cells and FcgammaRIIIA on NK cells obtained from TALs was significantly decreased in comparison to normal peripheral blood lymphocytes (PBLs): the mean fluorescence intensity of CD3 was 277 +/- 18 for TAL-T (n = 7) versus 349 +/- 13 for PBL-T (n = 9) and that of CD16 was 58 +/- 1 for TAL-NK (n = 7) versus 385 +/- 55 for PBL-NK (n = 23) cells. These observations suggest a defect in assembly of T cell receptor and FcgammaRIIIA multicomponent transmembrane receptors, which are zeta and gamma dependent. In addition to alterations in expression, the function of these receptors was also modified, since cross-linking of CD3 on TAL-T and CD16 on TAL-NK cells with the respective monoclonal antibodies resulted in a pattern of protein phosphorylation that was distinct from that observed in normal PBLs. Expression of tyrosine kinase p56(lck) and its kinase activity were also depressed, while expression of phospholipase C-gamma1 appeared to be normal in most preparations of the TALs tested. In vitro proliferation of TAL-T in response to anti-CD3 monoclonal antibody and TAL-NK cells to interleukin 2 were significantly depressed as was the ability to produce IFN-gamma. In contrast, TAL-T cells were able to produce interleukin 10 at levels similar to those secreted by normal PBLs. Thus, in TALs obtained from patients with advanced ovarian cancer, alterations in expression and activity of signaling molecules were associated with reduced cellular functions such as proliferation and production of certain cytokines.
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PMID:Alterations in expression and function of signal-transducing proteins in tumor-associated T and natural killer cells in patients with ovarian carcinoma. 981 3

We have performed a Phase I clinical trial with the naturally occurring flavonoid quercetin (3,3',4',5,7-pentahydroxyflavone). Quercetin has antiproliferative activity in vitro and is known to inhibit signal transduction targets including tyrosine kinases, protein kinase C, and phosphatidyl inositol-3 kinase. Quercetin was administered by short i.v. infusion at escalating doses initially at 3-week intervals. The first dose level was 60 mg/m2; at the 10th dose level of 1700 mg/m2, dose-limiting nephrotoxicity was encountered, but no myelosuppression. At the preceding dose level of 1400 mg/m2, five patients were treated at 3-week intervals, and another eight patients were treated on a once-weekly schedule; overall, 2 of 10 evaluable patients had renal toxicity, 1 at grade 2 and 1 at grade 4. We therefore treated other patients at 945 mg/m2 (eight at 3-week intervals and six at weekly intervals); 3 of 14 patients had clinically significant renal toxicity, 2 patients with grade 2 and 1 patient with grade 3. Patients treated on the weekly schedule did not have cumulative renal impairment but did have a fall in the glomerular filtration rate of 19 +/- 8% in the 24 h after drug administration. We recommend 1400 mg/m2 as the bolus dose, which may be given either in 3-week or weekly intervals, for Phase II trials. Quercetin pharmacokinetics were described by a first-order two-compartment model with a median t(1/2)alpha of 6 min and median t(1/2)beta of 43 min. The median estimated clearance was 0.28 liter/min/m2, and median volume of distribution at steady state was 3.7 liter/m2. In 9 of 11 patients, lymphocyte protein tyrosine phosphorylation was inhibited following administration of quercetin at 1 h, which persisted to 16 h. In one patient with ovarian cancer refractory to cisplatin, following two courses of quercetin (420 mg/m2), the CA 125 had fallen from 295 to 55 units/ml, and in another patient with hepatoma, the serum alpha-fetoprotein fell. In conclusion, quercetin can be safely administered by i.v. bolus at a dose injection. The plasma levels achieved inhibited lymphocyte tyrosine kinase activity, and evidence of antitumor activity was seen.
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PMID:Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. 981 16

The epidermal growth factor receptor (EGFR) is thought to mediate the action of the mitogens EGF and tumour growth factor-alpha (TGF-alpha) in a variety of cancers, including those of the lung, breast and ovary. A number of new selective inhibitors of EGFR tyrosine kinase have now been developed as potential new antitumour agents. We used a potent inhibitor of this tyrosine kinase, 6-amino-4-[(3-bromophenyl)amino]-7-(methylamino)quinazoline (SN 25531; PD 156273), to determine the responses of primary cultures derived from patients with cancer of the lung, ovary, breast, cervix and endometrium. Cells were cultured in 96-well plates and proliferation assessed by incorporation of 3H-thymidine. Measured growth inhibitory concentrations IC50 values) varied from 1 nM to 14 microM with a 1000-fold differential between sensitive and resistant cultures. Results were compared with rates of proliferation, estimated using a paclitaxel-based method. We also measured the IC50 values for the tyrosine kinase inhibitor using a number of established human cell lines, and compared them with EGFR content using fluorescent antibody staining and flow cytometry. The presence of EGFR was found to be necessary, but not sufficient, for in vitro response. Only a small number of cell lines (3 of 7 for lung, 1 of 7 for ovarian, 2 of 3 squamous cell and 0 of 12 for melanoma) were sensitive to the tyrosine kinase inhibitor. In contrast, 40 of the 50 primary cultures (including 14 of 15 lung cancer samples and 14 of 19 ovarian cancer samples) were sensitive.
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PMID:Inhibition of growth of primary human tumour cell cultures by a 4-anilinoquinazoline inhibitor of the epidermal growth factor receptor family of tyrosine kinases. 984 59

Overexpression of the c-erbB-2 (HER-2/neu) oncogene, which encodes a transmembrane receptor tyrosine kinase, has been shown to be associated with poor prognosis in ovarian and breast cancer. Recent studies indicate that c-erbB-2 may also be involved in determining the chemosensitivity of human cancers. In the present study, we examined the role of c-erbB-2 for chemoresistance in ovarian cancer. Overexpression of c-erbB-2 mRNA in tumor tissue was associated with a shorter survival of patients with primary ovarian cancer (P = 0.0001; n = 77) and was an independent prognostic factor in the proportional-hazard model adjusted for International Federation of Gynecologists and Obstetricians stage, residual disease, chemotherapy, and age (P = 0.035). A significant association between expression of c-erbB-2 mRNA and survival was obtained for the subgroup of patients who received a standard chemotherapy with carboplatin or cisplatin and cyclophosphamide (P = 0.0003), whereas only a nonsignificant trend was observed for patients who did not receive a standard chemotherapy (P = 0.124). In addition, the application of a standard chemotherapy improved the survival of patients with relatively low c-erbB-2 expression (P = 0.013) but not of patients with overexpression of c-erbB-2 (P = 0.359). Expression of c-erbB-2 mRNA correlated with expression of topoisomerase IIalpha mRNA determined by a reverse semiquantitative PCR technique (P = 0.009), whereas expression of c-erbB-2 and topoisomerase IIbeta mRNA did not correlate (P = 0.221). To examine the hypothesis that coamplified and/or coregulated topoisomerase IIalpha contributes to the resistance of c-erbB-2-overexpressing carcinomas, we established a chemosensitivity assay using primary cells from an ovarian carcinoma that overexpressed both c-erbB-2 and topoisomerase IIalpha. The combination of carboplatin with nontoxic concentrations of the topoisomerase II inhibitors etoposide or novobiocin enhanced the toxicity of carboplatin. In contrast, the tyrosine kinase inhibitor emodin exhibited no chemosensitizing effect in cells of this individual carcinoma. In conclusion, overexpression of c-erbB-2 was associated with poor prognosis and poor response to chemotherapy. The data suggest that topoisomerase IIlalpha, which correlates with c-erbB-2 expression, contributes to the resistance of c-erbB-2-overexpressing carcinomas.
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PMID:Contribution of c-erbB-2 and topoisomerase IIalpha to chemoresistance in ovarian cancer. 1039 67

The Src protein tyrosine kinase is overexpressed and activated in a number of human cancers, including some human ovarian cancers. To determine whether Src activity plays a role in ovarian tumor growth, stable derivatives of the SKOv-3 human ovarian cancer cell line that exhibited reduced Src tyrosine kinase activity were generated by transfection with an antisense c-src construct. Comparison of these cell lines with parental SKOv-3 cells and stable sense c-src vector-transfected control lines revealed no phenotypic alterations in anchorage-dependent proliferation, adherence, density saturation, or wound migration. However, reduction in Src activity was associated with altered cellular morphology, dramatically reduced anchorage-independent growth, and, when assessed for tumor development in a xenograft nude mouse model, diminished tumor growth. Furthermore, reduction of Src activity in the antisense c-src cell lines was associated with reduced vascular endothelial growth factor mRNA expression in vitro, and tumors derived from these cell lines displayed a phenotype indicative of abortive microvessel vascularization. These results strongly suggest that Src is involved in critical oncogenic pathways that modulate tumor growth from this ovarian cell line. Furthermore, this evidence suggests that as in other tumor systems, Src activity is required for vascular endothelial growth factor induction and angiogenic development.
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PMID:Decreased Src tyrosine kinase activity inhibits malignant human ovarian cancer tumor growth in a nude mouse model. 1047 1

Expression of the RIalpha subunit of cAMP-dependent protein kinase type I is increased in human cancers in which an autocrine pathway for epidermal growth factor-related growth factors is activated. We have investigated the effect of sequence-specific inhibition of RIalpha gene expression on ovarian cancer cell growth. We report that RIalpha antisense treatment results in a reduction in RIalpha expression and protein kinase A type I, and inhibition of cell growth. The growth inhibition was accompanied by changes in cell morphology and appearance of apoptotic nuclei. In addition, EGF receptor, c-erbB-2 and c-erbB-3 levels were reduced, and the basal and EGF-stimulated mitogen-activated protein kinase activities were reduced. Protein kinase A type I and EGF receptor levels were also reduced in cells overexpressing EGF receptor antisense cDNA. These results suggest that the antisense depletion of RIalpha leads to blockade of both the serine-threonine kinase and the tyrosine kinase signaling pathways resulting in arrest of ovarian cancer cell growth.
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PMID:Protein kinase A-Ialpha subunit-directed antisense inhibition of ovarian cancer cell growth: crosstalk with tyrosine kinase signaling pathway. 1049 Aug 35

We determined whether inhibition of the catalytic tyrosine kinase activity of the receptors for vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) inhibits the formation of malignant ascites and the progressive growth of human ovarian carcinoma cells implanted into the peritoneal cavity of nude mice. The novel protein tyrosine inhibitor PTK 787 was evaluated in two models of human ovarian cancer: Hey-A8 cells, which express low levels of VEGF/VPF and grow as solid tumor foci on the surface of peritoneal organs, and SKOV3 i.p.1 cells, which express high levels of VEGF/VPF and grow as solid peritoneal tumors and ascites. Treatment of nude mice by daily oral administration of 50 mg/kg PTK 787 was not effective against Hey-A8 tumors. In sharp contrast, it significantly inhibited growth of SKOV3 i.p.1 cells and formation of ascites, significantly increasing survival of mice with the implants. Tumor-induced vascular hyperpermeability in the peritoneum of tumor-bearing mice was inhibited by PTK 787, which accounted for its inhibition of ascites formation. Our results suggest that blockade of the VEGF/VPF receptor may be an efficient strategy to inhibit formation of malignant ascites and growth of VEGF/VPF-dependent human ovarian carcinomas.
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PMID:Inhibition of malignant ascites and growth of human ovarian carcinoma by oral administration of a potent inhibitor of the vascular endothelial growth factor receptor tyrosine kinases. 1067 74

The U6 expression system was explored for efficient expression of a ribozyme against the human proto-oncogene c-neu. A hammerhead ribozyme (neuRz) and the control mutant ribozyme (MRz) were targeted to cleave c-neu mRNA at the tyrosine kinase domain. In vitro cleavage showed that neuRz was very active while MRz was not. Near-maximal target cleavage observed at a low ribozyme:target ratio (0.1) suggests that neuRz has good activity and turnover capability under physiological conditions, i.e., <5 mM MgCl(2) and 37 degrees C. Chimeric U6 ribozyme was expressed at about 5 x 10(6) copies/cell at 48 h in the ovarian carcinoma cell line SKOV-3.ip1. Partial down-regulation of c-neu mRNA and protein was observed in a dose-dependent manner in cells transiently transfected with U6neuRz- but not with MRz-containing plasmid. Sorted transient transfectants demonstrated dramatic growth inhibition with the neuRz-expressing cells. Our results demonstrate that the U6 expression system is very efficient and suitable for the expression of a hammerhead ribozyme. Moreover, nonviral delivery of the neuRz-expressing plasmid resulted in specific down-regulation of c-neu and, subsequently, growth inhibition of ovarian cancer cells overexpressing c-neu.
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PMID:Specific down-regulation of HER-2/neu mediated by a chimeric U6 hammerhead ribozyme results in growth inhibition of human ovarian carcinoma. 1123 73

The c-erbB-2 oncogene encodes a tyrosine kinase that constitutes the internal and transmembrane part of the epidermal growth factor receptor (EGFR). ErbB-2 overexpression has been reported in 20% to 30% of human adenocarcinomas of the breast and ovary, and has been linked to an unfavorable prognosis in patients. Hypericin is a protein tyrosine kinase inhibitor that has been exploited in models for anti-tumor and anti-viral activity. In this study, we investigated the effects of hypericin on the activity of the c-erbB-2 oncoprotein and its downstream kinases. We also investigated the effect of hypericin on metastasis. We used ovarian SK-OV-3 cells as a model to determine whether hypericin-induced cell death was associated with inhibition of c-erbB-2 expression and activation. The IC50 of hypericin after 72 hrs exposure was 7.5 microM as determined by the MTT assay. Apoptosis, which was assessed by morphological changes and a flow cytometric assay, was observed at 24 h after continuous exposure to 5 microM hypericin. Inhibition of expression of the c-erbB-2 protein was detected, using a monoclonal anti-erbB-2 antibody after 12-48 hrs of exposure to hypericin. Hypericin was found to inhibit autophosphorylation of the erbB-2 protein and downstream kinases such as MEK and ERK1/2. We also found up-regulation of p21WAF1 expression and down-regulation of Bcl-2 in hypericin treated cells. An invasion assay showed that hypericin inhibited the movement of SK-OV-3 cells into the Matrigel. However, gelatin zymography showed that hypericin had no effect on the secretion of matrix metalloproteinases (MMPs) in SK-OV-3 cells. From these results, we conclude that hypericin inhibits the growth of SK-OV-3 ovarian cancer cells, inhibits the autophosphorylation of c-erbB-2, induces apoptosis, and may inhibit invasion.
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PMID:Inhibition of c-erbB-2 expression an activity in human ovarian carcinoma cells by hypericin. 1172 34

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