Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monoclonal antibody-based therapeutics are beginning to realize the promise that was predicted with the advent of the core technology more than 20 years ago. Antibody-based therapeutics targeting tumor cell surface antigens such as B-cell idiotypes, CD20 on malignant B cells, CD33 on leukemic blasts, and HER2/neu on breast cancer cells have shown efficacy in clinical trials. Multiple antibody-based strategies have shown promising efficacy in recent clinical trials. Unconjugated immunoglobulins directed against CD20 induce partial and complete responses in up to 50% of patients with advanced, indolent non-Hodgkin's lymphoma When such antibodies are conjugated to appropriate radionuclides and administered in therapeutic doses, the proportions of complete and overall responses increase considerably. Conjugates composed of anti-CD33 antibodies and the chemotherapy agent, calicheamicin, show promising activity in patients with relapsed or refractory acute myelogenous leukemia. Treatment of patients with advanced breast cancer using the anti-HER2/neu antibody trastuzumab (Herceptin; Genentech, San Francisco) leads to objective responses in some patients whose tumors overexpress the HER2/neu oncoprotein. These exciting results justify recent enthusiasm for continued efforts to refine existing approaches and to develop new antibody-based strategies to treat human malignancy.
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PMID:An overview of monoclonal antibody therapy of cancer. 1048 93

The HER2/neu proto-oncogene is overexpressed in 25% to 30% of patients with breast cancer. Trastuzumab (Herceptin; Genentech, San Francisco, CA), a recombinant humanized monoclonal antibody with high affinity for the HER2 protein, inhibits the growth of breast cancer cells overexpressing HER2. In this phase II study the efficacy and toxicity of weekly administration of trastuzumab was evaluated in 46 patients with metastatic breast cancer whose tumors overexpressed HER2. A loading dose of 250 mg trastuzumab was administered intravenously, which was followed by 10 weekly doses of 100 mg each. Upon completion of this treatment period, patients with no disease progression could receive a weekly maintenance dose of 100 mg. Patients in this trial had extensive metastatic disease, and most had received prior anticancer therapy. Ninety percent of patients achieved adequate serum levels of trastuzumab. Toxicity was minimal, and no antibodies against trastuzumab could be detected. Objective responses were observed in 5 of the 43 evaluable patients, which included 1 complete remission and 4 partial remissions, for an overall response rate of 11.6%. Responses were seen in mediastinum, lymph nodes, liver, and chest wall lesions. Minor responses (seen in 2 patients) and stable disease (14 patients) lasted for a median of 5.1 months. These results demonstrate that trastuzumab is well tolerated and clinically active in patients with HER2-overexpressing metastatic breast cancers who have received extensive prior therapy. The regression of human cancer through the targeting of putative growth factor receptors such as HER2 warrants further evaluation of trastuzumab in the treatment of breast cancer.
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PMID:Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer. 1048 97

Monoclonal antibody therapy is beginning to realize its promise. Efficacy has been seen in clinical trials using antibodies that target tumor cell surface antigens such as B-cell idiotypes, CD20 on malignant B cells, CD33 on leukemic blasts, and HER2/neu on breast cancer. Unconjugated immunoglobulins directed against CD20 induce partial and complete responses in up to 50% of patients with advanced, indolent non-Hodgkin's lymphoma. When such antibodies are conjugated to radionuclides, complete and overall response rates increase. Conjugates composed of anti-CD33 antibodies and the chemotherapy agent, calicheamicin, show promising activity in patients with relapsed or refractory acute myelogenous leukemia Treatment of patients with advanced breast cancer using the anti-HER2/neu antibody, trastuzumab (Herceptin; Genentech, San Francisco, CA) leads to objective responses in some patients with overexpression of the HER2/neu oncoprotein. These exciting results provide a basis for further refinement of the existing approaches to develop new antibody-based cancer therapy strategies.
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PMID:Monoclonal antibody therapy of cancer. 1056 Oct 17

Herceptin (trastuzamab, Genentech, San Francisco, CA, USA) prolongs survival in metastatic breast cancer patients whose tumours overexpress the HER2/neu protein. Compared with chemotherapy alone, patients receiving chemotherapy and Herceptin have a significantly longer time to progression, a higher response rate and a longer duration of response. These effects are most marked in first-line treatment of metastatic disease. The addition of Herceptin is associated with few additional side-effects, apart from cardiac toxicity in patients concurrently receiving anthracyclines. As such, it seems reasonable for Herceptin to become considered as one of the routine treatment options in metastatic breast cancer. It would therefore be appropriate for HER2 status testing to be incorporated into the assessment of all patients with metastatic disease. The use of this medication will be limited by its cost. Furthermore, data are lacking on appropriate treatments durations in responders.
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PMID:Herceptin (trastuzamab) in advanced breast cancer. 1091 83

Several recent advances have led to accelerated progress in breast cancer therapy. The development of new drugs with novel mechanisms of action, such as the taxanes, or oral bioavailability, such as capecitabine, has expanded the horizons of available chemotherapy. The use of tumor-related proteins or genes as markers of sensitivity or resistance to systemic therapy may allow for more predictable outcomes. Finally, the emergence of biological therapies such as the HER2/neu monoclonal antibody trastuzumab (Herceptin; Genentech, Inc, So. San Francisco, CA) represents an exciting new direction that opens doors to new concepts in antitumor therapy. This report will review the most exciting possibilities for expanding the field of breast cancer management.
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PMID:State-of-the-art chemotherapy for advanced breast cancer. 1104 51

The physical characteristics of tumor antigens that would make the most ideal targets for antibody therapeutics include cell surface expression; high, stable expression levels in tumor cells; low or absent expression in normal tissues; lack of a soluble form of the antigenic target; and lack of internalization of the antigen/antibody complex. HER2/neu is a 185-kd surface membrane protein that is overexpressed in approximately 25% of human breast cancers due to amplification of the HER2 gene. Overexpression of the gene results in ligand-independent activation of HER2 kinase, causing mitogenic signal transduction and increased cell proliferation. Consequently, patients with this alteration have a worse clinical prognosis. Trastuzumab (Herceptin; Genentech, Inc, So. San Francisco, CA), a humanized anti-HER2 monoclonal antibody, has significant clinical activity against metastatic breast cancers with HER2/neu overexpression, despite the fact that the p185HER2 protein product lacks some of the ideal characteristics of tumor antigens listed above. We propose that the efficacy of trastuzumab may be explained on the basis of its effects on signal transduction, which is independent from its immune mechanism(s) of action. Furthermore, trastuzumab is synergistic with some chemotherapeutic drugs, resulting in improved therapeutic efficacy. Thus, in the case of trastuzumab, a clear distinction may be drawn between the use of monoclonal antibodies as immuneactive agents and their use to achieve a desired cellular/biochemical activity.
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PMID:Biological rationale for HER2/neu (c-erbB2) as a target for monoclonal antibody therapy. 1104 52

The HER2 gene (also known as neu and as c-erb-B2) encodes a 185-kd transmembrane glycoprotein receptor with intrinsic tyrosine kinase activity. HER2 is overexpressed in 25% to 30% of human breast cancers, plays a role in the pathogenesis of breast cancer, and predicts for a worse prognosis in patients with metastatic disease. Trastuzumab (Herceptin; Genentech, Inc, So. San Francisco, CA), a humanized monoclonal antibody that targets the HER2 oncogene receptor, was shown to be active in preclinical models. In initial phase I clinical trials, trastuzumab was found to be safe and to exhibit dose-dependent pharmacokinetics. Three phase II studies of single-agent trastuzumab, which was administered weekly in the outpatient setting, have now been conducted in patients with HER2-overexpressing metastatic breast cancer. In the initial phase II study, the response rate was 11% in a heavily pretreated patient population. In a pivotal follow-up study of single-agent trastuzumab, more than 200 patients who had received at least one prior chemotherapeutic regimen for metastatic disease were entered. Despite a number of unfavorable baseline characteristics, the response rate reported by an independent response evaluation committee was 15%. A more recent study in previously untreated patients has shown a 23% response rate. The median duration of response in these trials has ranged from 6.6 to 9.1 months. In these three phase II studies, trastuzumab has been shown to be safe. The most clinically significant adverse event has been cardiac dysfunction syndrome, which occurred in less than 5% of patients. Trastuzumab is not associated with the other commonly observed side effects of chemotherapy, such as alopecia, mucositis, and neutropenia. The results from these studies demonstrate that trastuzumab is active and safe in patients with metastatic HER2-overexpressing breast cancer.
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PMID:Clinical trials of single-agent trastuzumab (Herceptin). 1104 53

HercepTestTM (DAKO A/S, Glostrup, Denmark) is an immunohistochemical assay that detects HER2/neu gene products, and evaluates the overexpression status of the HER2/neu protein in determining eligibility for the Trastuzumab (HerceptinR, Genentech, San Francisco, CA, USA) therapy. However, practically, interobserver variability of the HER2/neu interpretation of the immunostained results has caused marked disagreement with regard to the intensity of tumor staining. In this study, we quantitated HER2/neu expression by image analysis, and applied this analyzing system to help to minimize interobserver variability of the interpretation of the HercepTestTM. All the immunostained results were scored semiquantitatively on a range of 0 to 3+ in accordance with the criteria described as per the manufacturer's instructions, and quantitatively evaluated using an image analyzing system with image processing software. Among the 92 cases, 15 were scored as 3+, six were 2+, and 32 were 1+ under intraobservers agreement. When the cases were quantitated, a high correlation was shown between the signal area extracted by image analysis and the corresponding score of staining intensity with the HercepTestTM. By converting the quantitatively extracted data into a scoring system based upon the criteria, the outcome demonstrated a strong concordance with the scoring data obtained from immunostaining. The results indicated that a quantitative scoring system performed by simple image analysis may provide to improve interobserver agreement of the interpretation of the HercepTest TM in clinical practice.
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PMID:Quantitative immunohistochemical evaluation of HER2/neu expression with HercepTestTM in breast carcinoma by image analysis. 1114 61

HER-2 (c-erbB-2, neu) is an important prognostic and predictive factor in breast cancer. Clinical trials utilizing a humanized version of the anti-HER-2 murine monoclonal antibody 4DS, trastuzumab (Herceptin; Genentech Inc, South San Francisco, CA), have shown antitumor activity in patients with HER-2-positive metastatic breast cancer. Improved response and survival rates have been shown when trastuzumab was added to first-line combination chemotherapy with anthracycline/cyclophosphamide or paclitaxel, compared to the same chemotherapy alone. The Breast Cancer Intergroup has recently completed several trials evaluating new chemotherapy treatment approaches for patients with node-positive breast cancer, which form the basis for several ongoing and planned clinical trials incorporating trastuzumab. These clinical trials and the evolving role of trastuzumab-containing adjuvant systemic therapy for breast cancer will be reviewed.
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PMID:Ongoing and planned adjuvant trials with trastuzumab. 1123 24

Abnormalities in the expression, structure, or activity of proto-oncogene products contribute to the development and maintenance of the malignant phenotype. For example, c-erbB-2 encodes the HER-2 receptor (also known as c-erbB-2 or c-neu) that is overexpressed, amplified, or both in a number of human malignancies including breast, ovarian, colon, lung, prostate, and cervical cancers. In addition to deregulation of cell-surface HER receptors, cancer cells often show excessive activation and/or nonattenuation of growth factor--inducible signaling components, as well as their downstream transcription factors. Current approaches to target HER-2 pathways include downregulation of HER-2 by the adenovirus 5E1A, antisense phosphothionate oligonucleotides, ribozyme, and targeting tyrosine kinase using specific inhibitors. Because growth factors regulate the proliferation of cancer cells by activating receptors on the surface of cells, one obvious approach to control cell proliferation is to interfere with the growth factor receptor-mediated autocrine/ paracrine growth stimulation by antireceptor-blocking monoclonal antibodies. Therefore, a large number of scientists are attempting to control the growth of cancer cells using agents that inhibit one or more of the above steps of growth factor action. Recently completed clinical trials established the usefulness of a humanized form of 4DS monoclonal antibody, trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA), against some forms of breast tumors overexpressing HER-2 receptors. Using in vitro models, recent studies have shown that HER-2 overexpression may not be a prerequisite for invasion of breast cancer cells, as HER-2 activation by heregulin, which binds to HER-3 or HER-4 and transphosphorylates HER in noninvasive breast cancer cells, could lead to increased motility, enhanced gelatinolytic activity, and invasion. Furthermore, these ligand-driven phenotypic changes were completely suppressed by trastuzumab, which also blocked interactions between HER-2 and HER-3 receptors in heregulin-treated breast cancer cells, and inhibited the phosphatidylinositol-3' kinase-dependent pathway, but not the mitogen-activated protein kinase pathway. These phenotypic effects of anti-HER-2 monoclonal antibody are of special interest, because they point to potential therapeutic effects of trastuzumab in inhibiting the invasion and metastasis of breast cancer with low receptor expression.
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PMID:New insights into anti-HER-2 receptor monoclonal antibody research. 1123 33


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