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)

In order to study the influence of erbB-2 protein overexpression on outcome of patients with gastric cancer after attempted curative resection with or without adjuvant chemotherapy, paraffin embedded sections from 109 cases of primary gastric cancer with defined treatments have been immunostained for erbB-2 protein in a retrospective study. Thirty four cases (31%) showed strong membrane staining of tumor cells. erbB-2 overexpression did not show significant effect on outcome when all patients were considered. However, erbB-2 overexpression was an indicator for poor disease free survival (p = 0.0474), local relapse free survival (p = 0.0293), and overall survival (p = 0.0310) of the patients treated with surgery only (N = 51), while it did not show any effect on outcome of patients treated with 5-FU plus Doxorubicin (FA) as adjuvant chemotherapy (N = 58). Furthermore, the apparent therapeutic benefit from FA regimen was restricted to patients with erbB-2 positive tumors. Combined predictive value of erbB-2 and FA regimen was found to be significant in predicting local relapse in multivariate analysis (p = 0.0439). The data suggests that erbB-2 may be associated with an improved response to FA regimen and that erbB-2 should be included as a potential confounding variable in the analysis of the data from the clinical trials for gastric cancer.
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PMID:Overexpression of erbB-2 protein in gastric adenocarcinoma--a potential role in therapeutic response to adjuvant 5-FU-doxorubicin regimen. 135 36

Adriamycin (ADM) was chemically conjugated to a murine monoclonal antibody, A0011, which recognizes the c-erbB-2 product, via a disulfide bond using N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP) and 2-iminothiolane (2-IT). The molar ratio of ADM to the monoclonal antibody ranged from 15:1 to 25:1 and enzyme-linked immunosorbent assay (ELISA) showed that the binding activity of the conjugate was almost retained. We compared the efficacy of A0011 alone, ADM alone, the A0011-ADM conjugate, against the human breast cancer cell lines SK-BR-3, MDA-MB-361, MCF-7, and BT-20. The A0011-ADM conjugate was observed to be ten times more cytotoxic to the cell lines overexpressing the c-erbB-2 product, namely, SK-BR-3 and MDA-MB-361, than free ADM, but it showed weak cytotoxicity against the cell lines with a low level of c-erbB-2 product expression, namely, MCF-7 and BT-20. However, free A0011 and nonspecific murine IgM-ADM conjugate showed no cytotoxicity toward any of the four cell lines, while the addition of a tenfold molar excess of A0011 inhibited conjugate cytotoxicity. These data suggest that conjugate cytotoxicity is antibody-mediated. Moreover, conjugate cytotoxicity at 10(-6)M was correlated with antigen volume, and the data were fitted to the regression equation y = -11.63logX + 116.38 where the correlation coefficient = 0.950. Our results indicate that targeting therapy aiming at the c-erbB-2 product may be useful in the treatment of breast cancers overexpressing the c-erbB-2 product.
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PMID:Effectiveness of an adriamycin immunoconjugate that recognizes the C-erbB-2 product on breast cancer cell lines. 884 Apr 31

Doxorubicin shows a wide spectrum of activities in solid tumors, especially against breast carcinoma. The aim of this study was to examine if doxorubicin, when given at lower concentrations than applied in clinic, may induce changes in treated cells. With this purpose we developed human breast adenocarcinoma SK-BR-3 cell line resistant to doxorubicin. The sensitivity of these cells to doxorubicin and to some other cytostatics used in cancer treatment was determined by colorimetric MTT assay. Some parameters which may be of importance as prognostic factors in treatment of breast cancer were analyzed as well. The expression of genes involved in mitotic signal pathway (EGF, TGF alpha, EGF-R, erbB-2, erbB-3, c-myc and c-H-ras) was determined immunocytochemically. The concentrations of cathepsins were determined using quantitative immunoreactive assays (cathepsins B and L) or immunoradiometric assay (cathepsin D). The results revealed that even low doses of doxorubicin can induce numerous changes in treated cells: they become resistant to doxorubicin, and cross-resistant to several other cytostatics. The expression of the above mentioned genes involved in mitotic signal transduction, as well as cathepsins D and L, was similar in both parental and doxorubicin treated cells.
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PMID:Characterization of human breast adenocarcinoma SK-BR-3 cells resistant to doxorubicin. 937 56

Anti-HER2 immunoliposomes (ILs) have been constructed by conjugation of Fab' fragments of recombinant humanized monoclonal antibody rhuMAbHER2 to small sterically stabilized unilamellar liposomes, to create a targeted drug delivery vehicle for the treatment of HER2 (c-erbB-2, neu)-overexpressing cancers. Parameters affecting in vitro binding and internalization of ILs include liposome composition, Fab' linkage site and Fab' density. Anti-HER2 ILs have been constructed to optimize intracellular drug delivery. Doxorubicin (dox)-loaded ILs are highly stable and exhibit prolonged circulation in rats. In nude mice bearing HER2-overexpressing tumor xenografts, anti-HER2 ILs administered i.v. resulted in efficient tumor localization, with penetration of the ILs throughout the tumor mass and accumulation within tumor cells. In contrast, non-targeted liposomes resulted in extracellular tumor accumulation only. In multiple HER2-overexpressing human breast tumor xenograft models, treatment with dox-loaded anti-HER2 ILs produces significantly increased antitumor cytotoxicity as compared to free dox or dox-loaded non-targeted liposomes and significantly less systemic toxicity than free dox. To explore further the intracellular delivery advantages of ILs, anti-HER2 ILs bearing cationic lipids are being developed for nucleic acid delivery. These cationic immunoliposomes mediate efficient and specific transfection of target cells with reporter genes, as well as intracellular delivery of labeled oligonucleotides. Thus, anti-HER2 ILs represent an efficient and feasible strategy to achieve targeted intracellular delivery of therapeutic agents.
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PMID:Anti-HER2 immunoliposomes for targeted therapy of human tumors. 945 5

HER2 (erbB-2) proto-oncogene amplification and/or overexpression correlate with poor prognosis in many malignancies. The precise biological role of this oncogenic signaling pathway (which also involves the HER4 gene) in breast cancer is unclear. One property conferred by this oncogene relates to response to drug therapy. Clinical studies support an association between HER2 overexpression and resistance to alkylating agents (cisplatinum and cyclophosphamide). Data from the Cancer and Leukemia Group B 8869/8541 study indicate enhanced dose responsiveness to doxorubicin (Adriamycin) in patients who overexpress the HER2 receptor. Heregulin beta-2, a naturally occurring ligand that activates the HER2 receptor by inducing its heterodimerization with the HER4 receptor, has recently been cloned. The ability of this ligand to phosphorylate the HER2 receptor exogenously allows us to study the effect of HER2 activation on cancer cell behavior. To study the relationship between chemotherapy response and activation of HER2, MCF-7 cells expressing biologically active heregulin were assessed for response to doxorubicin and etoposide, both of which are topoisomerase IIalpha (topo IIalpha) inhibitors. Several clones show markedly increased sensitivity to these drugs. In addition, the same wild-type MCF-7 cells transfected with heregulin beta-2 under the control of an inducible promoter also show this dose-response relationship to doxorubicin after the expression of heregulin beta-2 is activated by zinc. The modulation of topo IIalpha was studied in the cell lines transfected with heregulin. topo IIalpha mRNA and protein (total protein and enzymatic decatenating activity) were found to be up-regulated in heregulin beta-2-transfected cells. Moreover, topo IIalpha promoter activity was also modestly increased in heregulin beta-2-transfected cells. Because up-regulation of topo IIalpha in vitro and in clinical specimens is associated with increased response to doxorubicin (presumptively by an increase in drug substrate), this may be the mechanism of the increased sensitivity to doxorubicin seen in heregulin beta-2-transfected cells. This implies that activation of HER2 or one of the other members of the receptor family may increase sensitivity to doxorubicin by up-regulation of topo IIalpha. This finding suggests the use of receptor/ligand expression to direct patient-specific therapeutic choices (e.g., doxorubicin versus alkylator-based regimens) and the use of biological agents (such as heregulin) in combination with certain chemotherapeutic agents to enhance response to treatment in breast cancer patients.
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PMID:Induction of sensitivity to doxorubicin and etoposide by transfection of MCF-7 breast cancer cells with heregulin beta-2. 956 96

Exposure of rat liver epithelial cells to doxorubicin, an anthraquinone derivative widely employed in cancer chemotherapy, led to a dose-dependent decrease in gap junctional intercellular communication (GJC). Gap junctions are clusters of inter-cellular channels consisting of connexins, the major connexin in the cells used being connexin-43 (Cx43). Doxorubicin-induced loss of GJC was mediated by activation of extracellular signal-regulated kinase (ERK)-1 and ERK-2, as demonstrated using inhibitors of ERK activation. Furthermore, activation of the epidermal growth factor (EGF) receptor by doxorubicin was responsible for ERK activation and the subsequent attenuation of GJC. Inhibition of GJC, however, was not by direct phosphorylation of Cx43 by ERK-1/2, whereas menadione, a 1,4-naphthoquinone derivative that was previously demonstrated to activate the same EGF receptor-dependent pathway as doxorubicin, resulting in downregulation of GJC, caused strong phos-phorylation of Cx43 at serines 279 and 282. Thus, ERK-dependent downregulation of GJC upon exposure to quinones may occur both by direct phosphorylation of Cx43 and in a phosphorylation-independent manner.
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PMID:Doxorubicin induces EGF receptor-dependent downregulation of gap junctional intercellular communication in rat liver epithelial cells. 1584 67