Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that O-phospho-L-tyrosine (P-Tyr), a substrate for a wide range of PTPases, inhibits the growth of human renal cell carcinoma and human breast cancer cell lines and suppresses EGF-mediated EGFR tyrosine phosphorylation. We now show that P-Tyr inhibited the growth of the human hepatoma cell line HEPG2, and src transformed NIH3T3 cells, but did not inhibit the growth of human ovarian carcinoma SKOV-3 cells. Addition of exogenous P-Tyr inhibited the insulin triggered insulin receptor (IR) tyrosine phosphorylation in the HEPG2 cell line and the tyrosine phosphorylation of a variety of cellular proteins in src-transformed NIH3T3 cells. P-Tyr did not inhibit the tyrosine phosphorylation of gp185 erbB-2 in P-Tyr resistant SKOV-3 cells. Thus, inhibition of cell growth by P-tyr was associated with decreased tyrosine phosphorylation of cellular proteins.
 ...
PMID:Association of inhibition of cell growth by O-phospho-L-tyrosine with decreased tyrosine phosphorylation. 860 80

The soluble ectodomain of c-erbB-2 oncoprotein was measured using a sandwich enzyme immunoassay in sera from 184 patients with renal cell carcinoma before initiation of treatment. The median serum level was 2062 U ml(-1) (range 865-4905 U ml(-1)). Levels were unaffected by sex, age and renal function. An inverse relation between disease stage (P = 0.0017) and tumour grade (P = 0.0009) and the serum level of c-erbB-2 ectodomain was observed. Survival time for patients with serum levels above median level was significantly longer than for patients with lower levels (P = 0.003). In a multivariate analysis, c-erbB-2 oncoprotein lost its prognostic information, while tumour stage and tumour grade were identified as independent prognostic factors.
 ...
PMID:Soluble ectodomain of c-erbB-2 oncoprotein in relation to tumour stage and grade in human renal cell carcinoma. 918 85

Receptor-mediated targeted tumor therapy is an important applied consequence of the studies on the genetic causes of cancer. These therapy concepts have to be evaluated in novel animal models that reflect the molecular aberrations found in human tumors. Here we introduce an animal model that allows the evaluation of drugs directed against a surface receptor that is frequently altered in primary human adenocarcinomas. Tumor toxins are polypeptides in which a tumor cell-specific recognition domain and a toxic effector domain have been joined by DNA recombination in vitro. Tumor cell recognition is contributed by a single-chain antibody domain specific for the extracellular domain of the erbB-2 receptor [scFv(FRP5)] and cytotoxicity by the enzymatically active domain of a bacterial exotoxin (exotoxin A from Pseudomonas aeruginosa). The erbB-2 receptor is overexpressed in many primary human cancer cells and is a favorable target for directed tumor therapy. The fusion protein scFv(FRP5)-exotoxin A has previously been shown to be able to efficiently and specifically kill erbB-2 receptor-expressing tumor cells. We have investigated the potential of this tumor toxin to detect and eliminate metastasizing tumor cells upon systemic administration. Murine renal carcinoma cells genetically modified with human erbB-2 receptor and bacterial beta-galactosidase genes form large pulmonary metastases when injected into the tail vein of BALB/c mice. Administration of the tumor toxin over a 10-day time period starting 1 day after tumor cell transplantation totally suppressed the formation of metastases. The treatment of animals 11 days after tumor cell transplantation, allowing the establishment of many pulmonary metastases, led to a drastic reduction in their number and size.
 ...
PMID:Systemic treatment with a recombinant erbB-2 receptor-specific tumor toxin efficiently reduces pulmonary metastases in mice injected with genetically modified carcinoma cells. 963 94

The epidermal growth factor (EGF) receptor and its ligand transforming growth factor-alpha (TGF-alpha) are overexpressed in human renal cell carcinoma (RCC). The chimeric anti-EGF receptor monoclonal antibody C225 was used to determine the effects of blocking the EGF receptor on RCC growth both in vitro and in vivo. A panel of RCC cell lines all tested positive at various levels for EGF receptor cell surface expression. C225 inhibited DNA synthesis of cultured A498, Caki-1, SK-RC-4, SK-RC-29, and SW839 cells in a dose-dependent manner, ranging from 20 to 45% inhibition compared with untreated controls. C225 also inhibited exogenous ligand-stimulated tyrosine phosphorylation of EGF receptor on RCC cells. The antitumor effects of C225 on RCC tumor growth were evaluated in ascites, s.c., and orthotopic RCC xenograft models. Mice treated with C225 in a Caki-1 ascites xenograft model showed a significant increase in survival (P = 0.002). All control mice died with ascites tumors by week 9, whereas >70% of C225-treated mice survived beyond 12 weeks. C225 also inhibited the growth of s.c. SK-RC-29 tumors in a dose-dependent manner. Mice treated with C225 (1 mg/dose) displayed a significant decrease in tumor volume compared with mice treated with control antibody (P < 0.05) or vehicle alone (P < 0.01). Lastly, C225 inhibited the growth and metastasis of RCC tumors growing orthotopically in the renal subcapsule of nude mice. Histological examination of RCC tumors from mice treated with C225 showed a substantial decrease in proliferating cell nuclear antigen staining and an increase in tumor cell apoptosis. These data suggest that C225 affects growth of RCC tumors by inhibiting EGF receptor-dependent proliferation and demonstrate the potential for therapeutic application of C225 in the treatment of human renal cancer.
 ...
PMID:Mouse-human chimeric anti-epidermal growth factor receptor antibody C225 inhibits the growth of human renal cell carcinoma xenografts in nude mice. 986 6

Blood lymphocytes of a HLA-A2 positive breast cancer patient were stimulated with either MCF-7 or MDA-MB-231, i.e., HLA-A2-matched allogeneic breast carcinoma cell lines. Several CD8+ CTL clones with reactivity against the stimulator cells but not against K562 were generated. Reactivity could be blocked with monoclonal antibody (mAb) W6/32, MA2.1, and/or BB7.2, indicating that the clones are HLA-class I and HLA-A2 restricted. The CTL clones generated following stimulation with MCF-7, recognized various other allogeneic HLA-A2+ tumor cell lines, including breast carcinoma, renal cell carcinoma, and melanoma cell lines, but not HLA-A2 tumor cell lines. The CTL clones did not recognize normal HLA-A2+ cells including breast epithelial cells, renal proximal tubular epithelial cells (PTEC), or EBV-transformed B cells including the autologous EBV cell line. In contrast to the CTL clones induced with MCF-7, the reactivity of the clones stimulated with MDA-MB-231, was limited to the stimulator cell MDA-MB-231. Cytotoxicity assays utilizing T2 cells loaded with peptides as target cells indicated that none of the examined CTL-epitopes derived from HER-2/neu, Muc-1, Ep-CAM-1, and p53 were recognized by the CTL clones generated. Our findings underscore that breast cancer is an immunogenic tumor and that HLA-class I-matched allogeneic tumor cells can be used as stimulator cells to generate tumor-specific CTL from peripheral blood of a breast cancer patient with specificity for an antigenic determinant that is broadly expressed on tumor cells from various origins or with specificity limited to the breast cancer stimulator cell.
 ...
PMID:Isolation of broadly reactive, tumor-specific, HLA Class-I restricted CTL from blood lymphocytes of a breast cancer patient. 1062 33

The HER-2/neu oncoprotein, a 185 kDa membrane-associated tyrosine kinase with extensive homology to the epidermal growth factor receptor (EGF-R), is overexpressed in breast and ovarian carcinomas. Its overexpression is closely associated with poor prognosis in the course of disease. Here we demonstrate HER-2/neu overexpression in both established cell lines and biopsy material obtained from renal epithelial tumors. Immunohistochemical analysis of human kidney tumor lesions using 2 HER-2/neu-specific antibodies revealed HER-2/neu expression in more than 40% of primary epithelial renal tumors and more than 30% of primary renal cell carcinoma (RCC) specimens. A distinctive HER-2/neu expression pattern was found in different subtypes of kidney tumors with the highest frequency in chromophilic and chromophobic RCC, but neither associated with disease stage nor tumor grade. Eight of 10 RCC cell lines expressed significant levels of HER-2/neu mRNA and protein, but at a lower level compared with HER-2/neu overexpressing ovarian carcinoma cells. To evaluate the immune response against HER-2/neu expressing HLA-A2-positive (HLA-A2(+)) RCC cells, allogeneic HLA-A2-restricted cytotoxic T-lymphocyte (CTL) lines generated by pulsing dendritic cells with 3 different HER-2/neu-derived peptides, (HER-2(9.369), HER-2(9.435) and HER-2(9.689), were utilized in chromium-release assays. Specific lysis of HER-2/neu expressing HLA-A2(+) RCC cell lines was mediated by CTL lines specific for each of these 3 HER-2/neu-derived epitopes. The fine specificity of 2 CTL clones was defined to the epitopes HER-2(9.435) and HER-2(9.689). Their specificity was then confirmed by cold target inhibition assays. In addition, CTL-mediated lysis was enhanced by pulsing tumor cells with exogenous HER-2/neu-specific peptides. Our data suggest that (i) HER-2/neu is heterogeneously expressed in different subtypes of RCC, (ii) HER-2/neu is naturally processed by RCC and (iii) HER-2/neu epitopes presented by RCC can be recognized by HLA-A2-restricted, HER-2/neu-specific CTL.
 ...
PMID:HER-2/neu is expressed in human renal cell carcinoma at heterogeneous levels independently of tumor grading and staging and can be recognized by HLA-A2.1-restricted cytotoxic T lymphocytes. 1089 39

HER-2/neu is a tumor-associated antigen overexpressed in a large variety of human tumors. Eight HER-2/neu peptides displaying HLA-A*0201 anchoring motifs were selected and tested for their binding affinity to HLA-A*0201 and their capacity to elicit cytotoxic T lymphocyte (CTL) responses in both HLA-A*0201 transgenic mice and in HLA-A*0201(+) healthy donors. Two high-affinity (p5 and p48) and one intermediate-affinity (p1023) peptides triggered CTL responses in both transgenic mice and humans, comparable to those observed for the well-known HER2/neu dominant peptide p369. CTL induced in transgenic mice lysed HLA-A*0201(+) RMA cells infected with recombinant HER-2/neu but not cells infected with wild-type vaccinia virus. Human CTL lysed HLA-A*0201(+) HER-2/neu(+) tumor cells of different origins (breast, colon, lung and renal cancer) irrespective of the expression levels of HER-2/neu. Importantly, primed CTL specific for these epitopes were detected in freshly isolated tumor-infiltrating lymphocytes from three renal cell carcinoma patients. Therefore, the HER-2/neu peptides p5, p48 and p1023 may be good candidates for immunotherapy of a broad spectrum of tumors, including renal cell carcinoma.
 ...
PMID:Identification of HER-2/neu immunogenic epitopes presented by renal cell carcinoma and other human epithelial tumors. 1174 43

Dendritic cells (DC) are the most potent APC with the unique capacity to initiate primary immune responses. For clinical use DC can be generated in vitro from CD34+ peripheral blood progenitor cells or monocytes. Vaccination of patients with cancer using DC was shown to be effective for B-cell lymphoma, renal cell carcinoma (RCC), prostate cancer and malignant melanoma. We provide evidence that patients with advanced breast and ovarian cancer can be efficiently vaccinated with autologous DC pulsed with HER-2/neu- or MUC1-derived peptides. In 5 of 10 patients, peptide-specific cytotoxic T lymphocytes (CTL) could be detected in the peripheral blood using both intracellular IFN-gamma staining and Cr-release assays. In addition, in one patient vaccinated with the MUC1-derived peptides, CEA- and MAGE-3 peptide-specific T-cell responses were detected after several vaccinations. In a second patient immunized with the HER-2/neu peptides, MUC1-specific T lymphocytes were induced after seven immunizations, suggesting that antigen spreading in vivo might occur after successful immunization with a single tumor antigen. Currently we are analyzing the effect of T-helper epitopes and IL-2 on the CTL induction using peptide pulsed DC. In this ongoing trial one patient with metastatic RCC developed a partial remission of the metastatic sites was induced after the first four vaccinations with MUC1 peptides pulsed DC, that was ongoing after the next cycles containing IL-2. Vaccine-induced peptide-specific T-cell responses in vivo were detected in the PBMNC of this patient and in peptide-specific DTH reactions. This studies demonstrate that peptide pulsed DC can be effective in cancer patients and induce significant clinical and immunological responses.
 ...
PMID:Dendritic cells in vaccination therapies of malignant diseases. 1235 54

The coexistence of multiple and synchronous primary neoplasms in the same organ (including kidney) has only rarely been described in the literature. We herein present a case of collecting duct carcinoma (CDC) combined with papillary renal carcinoma (RCC) having a 57-month disease-free survival CDC is a rather rare and aggressive neoplasm of the kidney. Sharing probably the same embryological origin, synchronous or metachronous association with in situ orpapillary transitional cell carcinoma (TCC) may be found; association with RCC has been only once reported in the literature. The high incidence of c-erbB-2 oncogene amplification in CDC further characterizes this tumor as a separate entity from renal cell carcinoma, and shows some genetic characteristics in common with TCC. The histological diagnosis of Bellini CDC can be confirmed by the positive immunohistochemical staining with a collecting duct marker and distal tubule marker and negative staining with a proximal tubule marker.
 ...
PMID:Synchronous collecting duct carcinoma and papillary renal cell carcinoma: a case report and review of the literature. 1581 31

The proangiogenic vascular endothelial growth factor-A (VEGF) is essential for the development of new tumor vessels. ZD6474 is a novel inhibitor of VEGF receptor-2 (VEGFR-2) tyrosine kinase activity, which also has additional activity against epidermal growth factor (EGF) receptor tyrosine kinase. The antitumor activity of different schedules of ZD6474 in a clinically relevant, metastasizing, murine renal cell carcinoma (RENCA) model was evaluated in this study. RENCA cells were inoculated into the left kidney of 24 mice (day 0). Daily ZD6474 (50 mg/kg p.o.) treatment was initiated 1 day or 10 days after tumor cell inoculation and continued until day 21. Following treatment, kidney weight and volume were assessed and blood vessel density determined by CD31 staining. Visible metastases in the lungs, spleen, and lymph nodes were quantified using a dissection microscope. In an additional study, animals were treated according to the same regimen and quantitative three-dimensional microvascular corrosion casting was performed to enable detailed assessment of the tumor vascular architecture. Therapy initiated on day 1 or day 10 resulted in a 79% and 59% reduction in primary tumor volume, a 79% and 60% reduction in the number of lung metastases, and a 58% and 59% reduction in vessel density of primary tumors compared with the control group, respectively. Corrosion casting proved a 5.4- and 3.2-fold lower vascular volume compared with untreated tumors, observations that paralleled with significant architectural alterations. In this RENCA model, ZD6474 was a highly active inhibitor of tumor angiogenesis, primary tumor growth and tumor metastasis.
 ...
PMID:The VEGF receptor tyrosine kinase inhibitor, ZD6474, inhibits angiogenesis and affects microvascular architecture within an orthotopically implanted renal cell carcinoma. 1588 78


<< Previous 1 2 3 Next >>