Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HER-2/neu oncogene encodes a transmembrane tyrosine kinase receptor with extensive homology to the epidermal growth factor receptor. HER-2/neu has been widely studied in breast cancer. In this review, the association of HER-2/neu gene and protein abnormalities studied by Southern and slot blotting, immunohistochemistry, enzyme immunoassays, and fluorescence in situ hybridization with prognosis in breast cancer is studied in depth by review of a series of 47 published studies encompassing more than 15,000 patients. The relative advantages of gene amplification assays and frozen/fresh tissue immunohistochemistry over paraffin section immunohistochemistry are discussed. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer are also considered. The potential value of HER-2/neu status for the prediction of response to therapy in breast cancer is presented in the light of a series of recently published studies showing a range of impact on the outcome of patients treated with hormonal, cytotoxic, and radiation therapies. The evidence that HER-2/neu gene and protein abnormalities in breast cancer predict resistance to tamoxifen therapy and relative sensitivity to chemotherapy regimens including adriamycin is presented. The review will also evaluate the status of serum-based testing for circulating the HER-2/neu receptor protein and its ability to predict disease outcome and therapy response. In the final section, the review will briefly present preliminary data concerning the use of antibody-based therapies directed against the HER-2/neu protein and their potential to become a new modality for breast cancer treatment. The recently presented phase III clinical trial evidence that systemic administration of anti-HER2 antibodies (Herceptin), alone and in combination with cytotoxic chemotherapy in patients with HER-2/neu overexpressing primary tumors, can increase the time to recurrence and overall response rates in metastatic breast cancer is reviewed.
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PMID:The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. 983 67

HER2 is overexpressed in about 25% to 30% of breast cancers and associated with poor prognosis, resistance to hormonotherapy and lack of sensitivity to CMF-based adjuvant chemotherapy. Herceptin (trastuzumab), a humanized monoclonal antibody, administered as a single agent, produces objective responses in phase II trials in patients with metastatic breast cancers overexpressing HER2. It has shown a substantial benefit in a phase III trial which compares a standard first line chemotherapy (doxorubicin and cyclophosphamide or taxol alone) to the same chemotherapy with Herceptin in metastatic breast cancer. The Herceptin arm had significantly higher response rate (+ 53%), an improvement in the median duration of response (+ 57%) as well as in time to progression (+ 65%) compared to chemotherapy alone.
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PMID:[Herceptin, a monoclonal humanized antibody anti-HER2: a major therapeutic progress in breast cancers overexpressing this oncogene?]. 1041 28

Low levels of p27Kip1 in primary prostate cancer specimens have been shown to be associated with higher rates of disease recurrence and poor rates of disease-free survival in patients with localized disease. In this study, we provide the first direct evidence showing that dihydrotestosterone (DHT), a major proliferation regulator of prostate cancer, can down-regulate p27Kip1 and stimulate cyclin-dependent kinase-2 (CDK2) activity in established prostate cancer cell lines. We investigated the cooperative effects of DHT and epidermal growth factor (EGF) on the proliferation of androgen-responsive MDA PCa 2a and MDA PCa 2b prostate cancer cells. DHT and EGF each stimulated proliferation of these cells, but exposure of the cells to DHT and EGF together stimulated greater proliferation. Stimulation of cell proliferation by DHT and/or EGF was associated with increased CDK2 activity and a decreased level of p27Kip1. There seems to be a positive feedback stimulation loop between androgen-induced gene transcription and EGF-stimulated signal transduction, as one could stimulate the synthesis of the receptors for the other. Dual blockade of androgen receptor function with the antiandrogen hydroxyflutamide and EGF receptor superfamily-mediated signal transduction with the anti-EGF receptor monoclonal antibody C225 and the anti-HER2 receptor monoclonal antibody Herceptin significantly enhanced growth inhibition of the MDA PCa 2a cells. Our results demonstrate the importance of counteracting both androgen receptors and EGF receptors in the development of novel therapies for prostate cancer.
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PMID:Androgen and epidermal growth factor down-regulate cyclin-dependent kinase inhibitor p27Kip1 and costimulate proliferation of MDA PCa 2a and MDA PCa 2b prostate cancer cells. 1047 2

The HER2 protein, a member of the epidermal growth factor family, is encoded by the protooncogene c-erbB-2. Its overexpression, occurring in approximately one-third of all breast carcinomas, is associated with a poor prognosis. A humanized mouse antibody against HER2 has been developed by genetic engineering. Here an unspecific human IgG was connected to the recognizing mouse IgG fragment. The allergization typical for allogeneic antibodies does not take place in this context. The effectiveness of this antibody has been confirmed by two international prospective phase III trials that tested it alone and combined with chemotherapy. Both modes of application increased the response rates and the time to progression. Side-effects were rare except for a high rate of cardiac dysfunction when the antibody was combined with anthracyclines. The effectiveness and negligible side-effects of the chimeric antibody against HER2 (Herceptin) render it a valuable tool in the treatment of breast cancer.
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PMID:Therapy of metastatic breast cancer with humanized antibodies against the HER2 receptor protein. 1048 Mar 46

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

HER2 is a ligand-less member of the human epidermal growth factor receptor or ErbB family of tyrosine kinases. In normal biological systems, HER2 functions as a co-receptor for a multitude of epidermal growth factor-like ligands that bind and activate other HER family members. HER2 overexpression is observed in a number of human adenocarcinomas and results in constitutive HER2 activation. Specific targeting of these tumors can be accomplished with antibodies directed against the extracellular domain of the HER2 protein. One of these antibodies, 4D5, has been fully humanized and is termed trastuzumab (Herceptin; Genentech, San Francisco, CA). Treatment of HER2-overexpressing breast cancer cell lines with trastuzumab results in induction of p27KIP1 and the Rb-related protein, p130, which in turn significantly reduces the number of cells undergoing S-phase. A number of other phenotypic changes are observed in vitro as a consequence of trastuzumab binding to HER2-overexpressing cells. These phenotypic changes include downmodulation of the HER2 receptor, inhibition of tumor cell growth, reversed cytokine resistance, restored E-cadherin expression levels, and reduced vascular endothelial growth factor production. Interaction of trastuzumab with the human immune system via its human immunoglobulin G1 Fc domain may potentiate its antitumor activities. In vitro studies demonstrate that trastuzumab is very effective in mediating antibody-dependent cell-mediated cytotoxicity against HER2-overexpressing tumor targets. Trastuzumab treatment of mouse xenograft models results in marked suppression of tumor growth. When given in combination with standard cytotoxic chemotherapeutic agents, trastuzumab treatment generally results in statistically superior antitumor efficacy compared with either agent given alone. Taken together, these studies suggest that the mechanism of action of trastuzumab includes antagonizing the constitutive growth-signaling properties of the HER2 system, enlisting immune cells to attack and kill the tumor target, and augmenting chemotherapy-induced cytotoxicity.
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PMID:Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). 1048 95

The recombinant humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin; Genentech, San Francisco, CA) was evaluated in human clinical trials for treatment of women with metastatic breast cancer who have tumors that overexpress HER2. The trastuzumab clinical program consisted of a series of phase I, phase II, and phase III clinical trials. Clinical experience with this novel biologic has been obtained in more than 1,000 women with HER2-overexpressing metastatic breast cancer. Two pivotal trials were performed to evaluate trastuzumab efficacy and safety: (1) trastuzumab in combination with chemotherapy as first-line therapy and (2) trastuzumab as a single agent in second- and third-line chemotherapy. Preliminary results of the pivotal clinical trials that have been presented at national meetings are summarized below. The data suggest that trastuzumab will be an important new treatment option for women with HER2-overexpressing metastatic breast cancer.
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PMID:Overview of the trastuzumab (Herceptin) anti-HER2 monoclonal antibody clinical program in HER2-overexpressing metastatic breast cancer. Herceptin Multinational Investigator Study Group. 1048 96

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

The measurement of health-related quality of life (HRQL) was an important component of clinical trials of trastuzumab (Herceptin; Genentech, San Francisco, CA) in women with progressive HER2-overexpressing metastatic breast cancer who may or may not have had prior chemotherapy. Health-related quality of life was measured at baseline and specified intervals during therapy using the European Organization for Research and Treatment of Cancer core Quality of Life Questionnaire (QLQ-C30, version 1.0). Five domains were chosen a priori for analysis: global quality of life, physical, role and social functioning, and fatigue. In the phase II study, in which trastuzumab was given alone, there was no change in on-treatment QLQ-C30 scores compared with baseline. These results suggest that trastuzumab does not adversely affect HRQL during therapy. In the phase III study, the effects of trastuzumab plus chemotherapy were compared with those of chemotherapy alone. A comparison of QLQ-C30 scores during treatment did not show statistically significant differences between the two groups at the preset level of P = .01. However, comparison of on-treatment scores with baseline in patients receiving chemotherapy alone indicated mild worsening of physical and role functioning and of fatigue throughout the duration of treatment, whereas a similar comparison of those receiving chemotherapy with trastuzumab revealed mild worsening of role functioning at weeks 8 and 20 and of fatigue only at week 8. These results suggest that trastuzumab may be associated with an amelioration of the deleterious effects of chemotherapy alone. In summary, in the doses and schedules used in these studies, trastuzumab is not associated with worsening of HRQL.
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PMID:Health-related quality of life in women with metastatic breast cancer treated with trastuzumab (Herceptin). 1048 98

Human epidermal growth factor receptor-2 (HER2) is a member of the epidermal growth factor receptor family, which produces factors that are considered to be important mediators of cell growth. Overexpression of HER2, which occurs in approximately 25% to 30% of human breast cancers, has fostered considerable interest in innovative therapeutic modalities designed to target tumor cells demonstrating such overexpression. Trastuzumab (Herceptin; Genentech, San Francisco, CA), a humanized monoclonal antibody developed to target the HER2 receptor, is the most widely studied example of such a modality. In early clinical studies with trastuzumab, cardiomyopathy was observed with a clinical expression similar to that seen with the anthracyclines (ie, a potentially progressive decrease in cardiac systolic function). A number of possible explanations for this cardiotoxicity are explored in this report. The first is that trastuzumab has inherent toxicity. This consideration has some theoretical interest, since fetal myocardial cells exhibit HER2 receptors and the adult myocardium expresses HER3 receptors. A second possibility is that sequential stresses following doxorubicin administration contribute to cardiac dysfunction. A third explanation is that observational artifacts lead to an overestimation of trastuzumab cardiotoxicity. Approaches for additional study of the extent and severity of trastuzumab cardiotoxicity are briefly addressed.
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PMID:Cardiotoxicity in patients receiving transtuzumab (Herceptin): primary toxicity, synergistic or sequential stress, or surveillance artifact? 1048


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