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

Expression of the product of the c-erbB-2 gene, a proto-oncogene related to, but distinct from c-erbB-1 encoding the epidermal growth factor receptor (EGF-R), was investigated in human urinary bladder carcinomas. In addition, levels of EGF-R and transferrin receptor were also analyzed using an immunohistochemical approach, and the results compared with histological pattern and grading, and tumor staging. Increased expression of c-erb B-2 product was found in 32% of cases (7/22), a positive reaction being observed in 60% of transitional cell carcinoma (TCC) Grade 3 lesions (3/5), 20% of Grade 2 TCCs (2/10) and 100% of adenocarcinomas (AC) (2/2), but in none of the cases of squamous cell carcinoma (SCC). Although no statistical correlation with staging was evident, TCCs or SCCs of high grade and stage often showed EGF-R-positive staining, whereas other well differentiated lesions and normal bladder epithelium were generally negative. Most cases of urinary bladder carcinoma were positive for the transferrin receptor, which was not detected in normal bladder. The results thus suggested that a positive reaction for c-erbB-2 product is correlated with TCC histological grading or AC morphology. A high intensity of EGF-R staining in human bladder carcinomas may be associated with poor differentiation and invasion, whereas transferrin receptor expression might reflect tumor growth.
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PMID:Immunohistochemical analysis of c-erbB-2 oncogene product and epidermal growth factor receptor expression in human urinary bladder carcinomas. 220 26

An immunotoxin was made by conjugating a murine monoclonal antibody (B4G7) that recognizes the human epidermal growth factor (EGF) receptor with gelonin, a ribosome-inactivating protein. This B4G7-gelonin conjugate was shown to be specifically cytotoxic for EGF receptor-hyperproducing cells. The conjugate was tested in nude mice and shown to be capable of suppressing the growth of an EGF receptor-hyperproducing squamous carcinoma cell (A431) solid tumor. Nude mice bearing an A431 cell tumor that were given injections i.p. for 5 consecutive days with at least 10 micrograms of the conjugate showed significant suppression of tumor growth for about 7 days. On the other hand, an unconjugated mixture of B4G7 and gelonin showed no specific antitumor activity against the A431 cell tumor. The growth of an EGF receptor-deficient small cell lung cancer cell (H69) tumor was not suppressed by injection of the conjugate. No toxic effects were observed in histological examination of nontumorous tissues of mice treated with at least 250 micrograms of conjugate per mouse. These results suggest that the conjugate may be useful for targeting therapy to EGF receptor-hyperproducing squamous carcinoma.
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PMID:Suppression of an epidermal growth factor receptor-hyperproducing tumor by an immunotoxin conjugate of gelonin and a monoclonal anti-epidermal growth factor receptor antibody. 255 59

Monoclonal antibodies (MoAbs) were developed against epidermal growth factor (EGF) receptor on the human epidermoid carcinoma cell line A431. The A431 antigen recognized by the MoAbs has an apparent molecular weight of approximately 170,000, with the same molecular weight as the CNE-2 cell line (poorly differentiated nasopharyngeal carcinoma). Administration of anti-EGF receptor MoAbs inhibited tumor formation, caused by the CNE-2 and A431 cell lines, in athymic mice. When the same MoAbs were used in therapy against Tca8113 (a human tongue carcinoma) and HeLa cells (a human cervical carcinoma), tumor growth was not affected. The number of EGF receptors and the apparent dissociation constants for 125I-EGF on CNE-2 and A431 were 1.3 x 10(5)/cell (Kd 7.7 x 10(-8) M) and 1.4 x 10(6)/cell (Kd 2.4 x 10(-9) M), respectively. Three anti-EGF receptor MoAbs were used in these studies. MoAbs 3 and 176, capable of competing with EGF for receptor binding, showed significant tumor growth inhibition. MoAb 101 was incapable of blocking the binding of EGF to its receptor and was not as effective as MoAbs 3 and 176 in tumor growth inhibition. Our observation is that in vitro, MoAb anti-EGF receptor is cytostatic, rather than cytocidal, against CNE-2 and A431.
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PMID:Growth inhibition of human nasopharyngeal carcinoma in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. 276 42

The HER-2/neu proto-oncogene is frequently amplified or overexpressed in many different types of human cancers, a phenomenon that has been shown to correlate with shorter survival time and lower survival rate in ovarian cancer patients. We previously reported that increased HER-2/neu expression led to more severe malignancy and increased metastatic potential in animal models and that the adenovirus 5 E1A gene repressed HER-2/neu gene expression at transcriptional level and was able to suppress tumor growth when stably transfected into human ovarian cancer SKOV-3 cells which overexpress HER-2/neu. To investigate whether the E1A gene may be used as a therapeutic agent for HER-2/neu-overexpressing human cancers in living hosts, we first developed tumor-bearing mice by injecting SKOV-3 cells that overexpress HER-2/neu intraperitonealy into female nu/nu mice. Five days later, we used cationic liposomes to directly deliver the E1A gene into adenocarcinomas that developed in the peritoneal cavity and on the mesentery of the mice that received the SKOV-3 cell injection. We found that liposome-mediated E1A gene transfer significantly inhibited growth and dissemination of ovarian cancer cells that overexpress HER-2/neu in the treated mice; about 70% of these mice survived at least 365 days, whereas all the control mice that did not receive the gene therapy developed severe tumor symptoms and died within 160 days. The results suggest that liposome-mediated E1A gene transfer may serve as an effective therapy for human ovarian cancers that overexpress HER-2/neu by directly targeting the HER-2/neu oncogene.
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PMID:Liposome-mediated in vivo E1A gene transfer suppressed dissemination of ovarian cancer cells that overexpress HER-2/neu. 747 60

The HER-2/neu (also named c-erbB-2) oncogene is known to be overexpressed in many human cancers, including breast, ovarian, lung, gastric and oral cancers. In animal models, HER-2/neu overexpression was shown to enhance malignancy and metastasis phenotypes. Repression of HER-2/neu overexpression suppresses the malignant phenotypes of HER-2/neu-overexpressing cancer cells, suggesting that HER-2/neu may serve as an excellent target for developing anti-cancer agents. We have previously shown that the adenovirus-5 (Ad5) E1a gene products and the SV40 large T antigen (large T) inhibit transcription of the HER-2/neu promoter and accordingly suppresses transformation induced by HER-2/neu. In this review, we summarize our recent findings on using cationic liposomes or an Ad vector to deliver E1a or large T into tumor-bearing mice. Our results indicate that both cationic liposomes or an Ad vector can efficiently deliver E1a or large T into tumor cells in mice, and this results in suppression of tumor growth and longer survival of the mice.
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PMID:HER-2/neu-targeting gene therapy--a review. 760 74

The HER-2/neu proto-oncogene encodes a transmembrane receptor protein whose expression is enhanced in a number of breast and ovarian tumors and correlates with tumor aggressiveness, suggesting that it may play an important role in tumor growth. Recent evidence suggests that HER-2/neu may be a potential candidate for targeted immune intervention. In this report we show that cytotoxic T lymphocytes (CTL) expanded from tumor-associated lymphocytes with HLA-A2+ and HER-2/neu+ tumors can specifically recognize synthetic peptides corresponding to amino acids 971-980 of HER-2/neu protein. This sequence includes a potential amphiphilic area containing both Rothbard's epitode motifs and HLA-A2 anchor residues. Our study provides the first direct evidence of HER-2/neu-reactive CTL in humans. The fact that these HER-2/neu peptide-reactive CTL show significantly lower reactivity with corresponding EGF-R peptides offers new perspectives for understanding the recognition of self-antigens by tumor-reactive T cells.
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PMID:Cytotoxic T cells isolated from ovarian malignant ascites recognize a peptide derived from the HER-2/neu proto-oncogene. 769 18

Overexpression of the c-erbB-2 protein (gp185c-erbB-2) is correlated with a tumorigenic phenotype and may contribute to disease progression. We have reported previously on an anti-gp185c-erbB-2 antibody, TAb 250, that inhibits in vitro and in vivo growth of breast and ovarian cell lines that overexpress the protein and enhances the inhibitory activity of cisplatin (CDDP). To assess whether CDDP resistance is related to gp185c-erbB-2 expression levels, alterations in tumor cell growth characteristics, or efficacy of antibody plus drug combination treatments, an SKOV-3 ovarian tumor cell line was made resistant to escalating doses of CDDP. Parental cells were 12-fold more sensitive to CDDP with 7 times more gp185c-erbB-2 sites than the most resistant variant (SKOV-3/C12). Additionally, the resistant cells demonstrated a longer lag phase for in vivo growth than the parental cells. While TAb 250 enhanced the in vivo inhibitory effect of CDDP against parental SKOV-3 cells, the antibody did not significantly alter the CDDP responsiveness of the resistant population. Growth inhibition by TAb 250 alone of both the parental and the SKOV-3-resistant variants was similar; however, TAb 250 was able to prolong the lag-phase of tumor growth of the resistant variant by up to 25 days. These results indicate that the development of CDDP resistance is associated with lowered levels of gp185c-erbB-2 expression, slower tumor cell growth, and enhanced efficacy of antibody treatment of the resistant cells.
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PMID:Development of resistance to cisplatin is associated with decreased expression of the gp185c-erbB-2 protein and alterations in growth properties and responses to therapy in an ovarian tumor cell line. 769 85

Amplification and overexpression of the erbB-2/neu protooncogene are frequently associated with aggressive clinical course of certain human adenocarcinomas, and therefore the encoded surface glycoprotein is considered a candidate target for immunotherapy. We previously generated a series of anti-ErbB-2 monoclonal antibodies (mAbs) that either accelerate or inhibit the tumorigenic growth of erbB-2-transformed murine fibroblasts. The present study extended this observation to a human tumor cell line grown as xenografts in athymic mice and addressed the biochemical differences between the two classes of mAbs. We show that the inhibitory effect is dominant in an antibody mixture, and it depends on antibody bivalency. By using radiolabeled mAbs we found that all of three tumor-inhibitory mAbs became rapidly inaccessible to acid treatment when incubated with tumor cells. However, a tumor-stimulatory mAb remained accessible to extracellular treatments, indicating that it did not undergo endocytosis. In addition, intracellular fragments of the inhibitory mAbs, but not of the stimulatory mAb, were observed. Electron microscopy of colloidal gold-antibody conjugates confirmed the absence of endocytosis of the stimulatory mAb but detected endocytic vesicles containing an inhibitory mAb. We conclude that acceleration of cell growth by ErbB-2 correlates with cell surface localization, whereas inhibition of tumor growth is associated with an intrinsic ability of anti-ErbB-2 mAbs to induce endocytosis. These conclusions are relevant to the selection of optimal mAbs for immunotherapy and may have implications for the mechanism of cellular transformation by an overexpressed erbB-2 gene.
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PMID:Suppression and promotion of tumor growth by monoclonal antibodies to ErbB-2 differentially correlate with cellular uptake. 772 65

Many human tumors over-express erbB-2 and EGF receptors. The membrane localization of these receptor tyrosine kinases make them appropriate targets for directed tumor therapy. We have used recombinant DNA technology to produce single-chain antibody exotoxin A (scFv-ETA) fusion proteins which specifically bind the erbB-2 and EGF receptors. The scFv portion is composed of the heavy- and light-chain variable domains of monoclonal antibodies which recognize the extracellular portion of each receptor. We have previously described the anti-tumor activity of the bacterially produced scFv(FRP5)-ETA directed to the erbB-2 receptor. In this paper we describe the characteristics of scFv(225)-ETA, a protein which binds the EGF receptor. The bacterially produced recombinant protein binds to the receptor with high affinity and inhibits the in vitro growth of the EGF receptor over-expressing tumor cell lines A431 and MDA-MB468. Combination treatment with scFv-(FRP5)-ETA and scFv(225)-ETA led to an additive inhibitory effect on the in vitro growth of A431 cells. SKBR3 cells expressing low levels of EGF receptor but high levels of p185erbB-2 were not affected by scFv(225)-ETA treatment but were sensitive to scFv(FRP5)-ETA. Stimulation of SKBR3 cells and HCII RI#11 mouse mammary epithelial cells expressing the human erbB-2 with EGF led to an increase in scFv(FRP5)-ETA activity, showing that the EGF-induced activation of erbB-2 can potentiate the action of the erbB-2-directed toxin. Treatment of athymic nude mice with scFv(FRP5)-ETA and the combination of both scFv-ETA proteins led to the transient arrest of growth of established A431 tumors. scFv(225)-ETA treatment alone was the most effective, leading to tumor shrinkage during the course of treatment, whereas treatment with the parental monoclonal antibody 225 led to retarded tumor growth.
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PMID:EGF receptor and p185erbB-2-specific single-chain antibody toxins differ in their cell-killing activity on tumor cells expressing both receptor proteins. 781 46

Two new human mammary carcinoma lines originating from surgical material were established in nude mice. According to the adopted criteria, the tumor 4049 has been classified as estradiol receptor positive and mammary carcinoma 4296 as estradiol receptor negative. Both tumors proved to be c-erbB-2 protein positive and EGF-receptor negative. In contrast to carcinoma 4296, the in vitro growth and the take rate of mammary carcinoma 4049 in nude mice seems to be dependent on stromal components. Pretreatment of mice with estradiol/peanut oil before tumor engraftment was an essential precondition for the growth of the primary tumor in nude mice. After successful establishment the tumor growth was significantly stimulated by estradiol. The growth rate of mammary carcinoma 4296 was independent of any supplementation of estradiol. The two breast tumors were characterized with regard to their growth behaviour, histology, and sensitivity to cytostatics and antihormones. They are considered suitable tumor models for the testing of antineoplastic substances and for biological experiments.
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PMID:Establishment and characteristics of two new human mammary carcinoma lines in nude mice with special reference to the estradiol receptor status and the importance of stroma for in vivo and in vitro growth. 786 48


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