Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

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

Improvements in breast cancer treatment will arrive with better understanding of its biology and through biologically oriented therapeutic interventions as well as better identification of patient populations susceptible to benefit from classical therapies (endocrine and chemotherapy). Among the new chemotherapies, the taxanes have emerged as powerful agents in the treatment of metastatic breast cancer and a strong emphasis has been pursued into their development in the adjuvant setting. Two generations of adjuvant pivotal trials with taxanes have been developed. The first generation compared taxane/anthracycline regimens to nontaxane combinations or sequence regimens. The second generation of trials is presently being performed and contains taxanes in both arms, comparing their use in combination or in sequence. Trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) is the first biologic modifier with significant activity in advanced breast cancer patients amplifying the HER2 gene. As a consequence of these results, including improved survival in the metastatic setting, this agent has been very quickly considered for adjuvant development. However, the significant cardiac toxicity observed with trastuzumab/anthracycline combinations has led to two main strategies for integrating trastuzumab in the adjuvant setting: (1) addition of trastuzumab to mostly anthracycline-based programs (sequential approach); and (2) biology-oriented strategy based on synergism between trastuzumab and chemotherapy agents. Large-scale clinical research programs are presently being developed and will create a challenge for clinical researchers. The adequate scientific hypothesis, related to the pivotal studies of trastuzumab in the adjuvant setting, require large sample sizes (several thousand patients) and a very strict selection of the patient population (tumors amplifying the HER2 gene). Success in a timely fashion requires global collaboration, dedication to high-standard clinical research, and awareness of all available protocols by oncologists and patients with breast cancer.
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PMID:New adjuvant strategies for breast cancer: meeting the challenge of integrating chemotherapy and trastuzumab (Herceptin). 1130 69

The discovery of the HER2/neu proto-oncogene and its role in the pathogenesis of breast cancer tumors, and the development of the anti-HER2 monoclonal antibody, trastuzumab (Herceptin; Genentech, South San Francisco, CA), directed against the HER2 receptor represent major milestones in the research developments in breast cancer, making trastuzumab the first monoclonal antibody available for treatment of this disease. Clinical trials in HER2-positive patients have demonstrated that the combined use of targeted therapy with trastuzumab in conjunction with cytotoxic chemotherapy is associated with improved time to disease progression and overall survival. Unfortunately, findings also demonstrate an increased risk for cardiotoxicity when trastuzumab is combined with anthracyclines. For HER2/neu-overexpressing breast cancer patients, the adjuvant use of trastuzumab will become paramount; therefore, it must be evaluated in a randomized controlled trial. There is disagreement regarding the design of such a trial, largely because of the ubiquitous use of anthracyclines in the adjuvant setting and the opposing necessity of avoiding anthracycline plus trastuzumab combinations. Combination index values for various chemotherapeutic drugs in combination with trastuzumab demonstrate dramatic synergistic interactions with the platinum agents and with docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Parsippany, NJ). The greatest level of synergy has been demonstrated with the triple-drug combination of docetaxel, platinum, and trastuzumab in which synergy is demonstrated, even at low doses. The adjuvant trial design for the Breast Cancer International Research Group uses a control arm of doxorubicin/cyclophosphamide for four cycles followed by docetaxel for four cycles and the second arm contains the addition of trastuzumab to the taxane sequence. The third arm, a non-anthracycline-containing regimen, contains docetaxel, a platinum agent (either cisplatin or carboplatin), and trastuzumab. The rationale for the selection of this three-drug regimen is based on the biology of the system and preclinical and clinical findings that demonstrate a high potential for clinical synergy.
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PMID:Rationale for trastuzumab (Herceptin) in adjuvant breast cancer trials. 1130 70

Trastuzumab (Herceptin; Genentech, South San Francisco, CA) is a humanized version of the murine monoclonal antibody 4D5 that was recently approved for the treatment of advanced breast cancer that overexpresses the HER2/neu oncogene. Cardiac toxicity was an unexpected side effect of trastuzumab treatment in the pivotal trials that led to its approval. The incidence of cardiac dysfunction was highly dependent on prior or concurrent doxorubicin exposure. For patients with minimal prior anthracycline exposure, the risk of cardiac dysfunction was 1%. For patients with more extensive prior doxorubicin exposure, the risk of cardiac dysfunction was 7% for trastuzumab monotherapy and 12% for trastuzumab plus paclitaxel (Taxol; Bristol-Myers Squibb Oncology, Princeton, NJ). For patients treated with trastuzumab concurrently with doxorubicin, the risk of cardiac dysfunction was 29%. The etiology of trastuzumab-associated cardiac dysfunction is unknown, although its dependence on concurrent or prior doxorubicin exposure suggests a common pathophysiologic basis with anthracycline-induced myocardial injury. A number of trials are in progress to evaluate the efficacy and safety of trastuzumab in patients with early stage disease and that will investigate novel strategies to circumvent this serious toxicity.
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PMID:Cardiac toxicity of trastuzumab (Herceptin): implications for the design of adjuvant trials. 1130 71

Metastatic breast cancer is a partially chemotherapy-sensitive neoplasm. Most chemotherapy groups have activity in this disease, and the most active single drugs are the taxanes, especially docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Parsippany, NJ), and the anthracyclines. The alkylating agents, antimetabolites, and vinca alkaloids are also widely used. The platinum coordination complexes, which are widely used in oncology, are also active in metastatic breast cancer, but the availability of other drugs that are less toxic and easier to administer has resulted in their having a strictly limited use in this setting. Cisplatin appears to be somewhat more active than carboplatin, but direct comparative studies are lacking. The identification of the prominent activity of the taxanes has led to the investigation of wholly novel non-anthracycline-containing combination regimens, and platinum/taxane doublets appear to be particularly active. More recently, reports that trastuzumab (Herceptin, Genentech, South San Francisco, CA), a novel monoclonal antibody directed against the protein product of the HER2/(neu) oncogene, has a powerful synergistic interaction with docetaxel and with platinum agents have prompted evaluation of the triplet docetaxel/platinum/trastuzumab in the therapy of metastatic breast cancer.
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PMID:The platinum agents: a role in breast cancer treatment? 1130 72

The rationale for the combined use of docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Parsippany, NJ) and trastuzumab (Herceptin; Genentech, South San Francisco, CA) in HER2/neu-overexpressing breast cancer patients are several-fold. Docetaxel is a highly active chemotherapeutic agent in metastatic breast cancer. Response rates, time to progression, and survival are improved when trastuzumab is combined with chemotherapy. Finally, preclinical findings demonstrate synergistic cytotoxic activity when docetaxel and trastuzumab are combined. In addition, their different mechanisms of action and a nonoverlapping toxicity profile suggest the potential for a highly useful combination while minimizing potential cardiotoxicity. An ongoing pilot phase II evaluation is being conducted with every-3-week docetaxel plus weekly trastuzumab. Preliminary findings suggest an active and well-tolerated regimen. Efficacy data indicate an encouraging overall major response rate of 45% in first- and second-line metastatic breast cancer patients. Preliminary results from a second phase II trial of weekly docetaxel and trastuzumab have been reported. In 14 patients treated to date, grade (3/4) toxicities are infrequent. An overall response rate of 54% is reported thus far with 26 cycles (156 weeks) of therapy delivered. The preliminary data for the docetaxel and trastuzumab combinations look favorable from both a safety and an efficacy perspective. The lack of cardiac function changes despite frequent cardiac monitoring is promising. For the adjuvant therapy of HER2/neu-overexpressing breast cancer, the high level of efficacy of docetaxel and the need to identify nonanthracycline agents for combined use with trastuzumab place a high emphasis on the potential utility of docetaxel and trastuzumab-based regimens.
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PMID:Docetaxel (Taxotere) plus trastuzumab (Herceptin) in breast cancer. 1130 73

HER2 is a ligand-less tyrosine kinase receptor of the ErbB family that is frequently overexpressed in breast cancer. It undergoes proteolytic cleavage that results in the release of the extracellular domain and the production of a truncated membrane-bound fragment, p95. We show that HER2 shedding is activated by 4-aminophenylmercuric acetate (APMA), a well-known matrix metalloprotease activator, in HER2-overexpressing breast cancer cells. The HER2 p95 fragment, which appears after APMA-induced cleavage, is phosphorylated. We analyzed 24 human breast cancer specimens, and a phosphorylated M(r) 95,000 HER2 band could be detected in some of them, which indicated that the truncated receptor is also present in vivo. The activation of HER2 shedding by APMA in cells was blocked with batimastat, a broad-spectrum metalloprotease inhibitor. Trastuzumab (Herceptin; Genentech, San Francisco, CA), a humanized monoclonal antibody directed at the HER2 ectodomain, which has been shown to be active in patients with HER2-overexpressing breast cancer, inhibited basal and induced HER2 cleavage and, as a consequence, the generation of phosphorylated p95. This inhibitory effect of trastuzumab was not shared by 2C4, an antibody against a different epitope of the HER2 ectodomain. The inhibition of basal and APMA-induced cleavage of HER2 by trastuzumab preceded antibody-induced receptor down-modulation, which indicated that the effect of trastuzumab on cleavage was not attributable to a decrease in cell-surface HER2 induced by trastuzumab. We propose that the inhibition of HER2 cleavage and prevention of the production of an active truncated HER2 fragment represent a novel mechanism of action of trastuzumab.
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PMID:Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. 1140 46

Gastrointestinal stromal tumor (GIST) has emerged in the past year as a prototypical neoplasm that responds to therapy directed against a single target molecule-the KIT receptor tyrosine kinase protein. Although GIST seldom responds to conventional chemotherapeutic agents, early experience with the tyrosine kinase inhibitor, STI-571 (Gleevec; Novartis, Basel, Switzerland), has been extremely encouraging. Early results have appeared in a recent case report in the New England Journal of Medicine (April 5, 2001),(1) and in early clinical trials from the United States and Europe that were reported at the plenary session of the American Society of Clinical Oncology in San Francisco on May 14, 2001. STI-571 is one of the earliest examples of a nontoxic chemotherapeutic agent (an agent whose anti-cancer activity is not predicated on a cytotoxic mechanism). STI-571 has already shown clinical value in BCR-ABL-positive leukemias. Early clinical results in GIST are so encouraging that oncologists may soon be wrestling with the opportunity of referring every patient with malignant GIST into clinical trials with STI-571. To ensure appropriate treatment, pathologists need to understand the biology and treatment of this tumor and to have standard methods and criteria for providing diagnosis (GIST or not GIST) and consistent prognostic classification (high risk of metastasis or low risk of metastasis).
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PMID:Gastrointestinal stromal tumor workshop. 1143 11

Overexpression of the HER2/neu oncogene (also known as c-erbB2) is a frequent molecular event in multiple human cancers, including breast and ovarian cancer. Patients with cancer that overexpress HER2/neu are associated with unfavorable prognosis, shorter relapse time, and low survival rate. Treatments that target HER2/neu expression in cancer cells have been shown to be useful strategies to significantly reverse the malignancy induced by HER2/neu overexpression. The humanized anti-HER2/neu antibody, trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) has proven to be effective in clinical trials in patients with metastatic breast cancer. In addition, tyrosine kinase inhibitors such as emodin can also target the HER2/neu oncogenic activity. Emodin treatment inhibits HER2/neu tyrosine kinase activity and preferentially suppresses the transformation of HER2/neu-overexpressing breast cancer cells. Emodin also sensitizes HER2/neu-overexpressing cancer cells to chemotherapeutic agents, including cisplatin, doxorubicin, etoposide, and paclitaxel. Alternatively, HER2/neu overexpression can be repressed by attenuating the promoter activity of the HER2/neu gene. We have identified a number of potent transcriptional regulators, including the ets family member PEA3 and the adenovirus type 5 E1A, which are able to repress HER2/neu gene expression. Expression of these transcriptional regulators resulted in downregulation of HER2/neu promoter activity and reversed the transformed phenotype of the cancer cells in vitro. In vivo studies show that these HER2/neu repressors can act therapeutically as tumor suppressor genes for tumors that overexpress HER2/neu. These preclinical studies clearly indicate that transcriptional repressors that downregulate HER2/neu can be effective regimens for cancer treatment in a gene therapy format. More importantly, the tumor-free survival rate of treated animals is dramatically increased under nontoxic doses compared with untreated animals. A phase I clinical trial using E1A-liposome in breast and ovarian patients has recently been completed. Following treatment, we observed downregulation of the HER2/neu protein accompanied by E1A expression in both cancer and noncancer cells. Numbers of tumor cells in the pleural effusion or ascites were found to be dramatically reduced after treatment. Furthermore, apoptosis was strongly induced in the tumor cells. A phase II study has been started to further evaluate therapeutic efficacy and tumor suppression mechanisms of E1A. These studies show the clinical potential of targeting HER2/neu in cancer therapy.
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PMID:Targeting HER2: recent developments and future directions for breast cancer patients. 1177 2

HER2/neu amplification/overexpression confers more aggressive and malignant characteristics on breast cancer cells. Patients with HER2/neu-amplified breast cancer have a worse prognosis than those with normal HER2/neu expression. Over the past decade, the intracellular signaling pathways associated with this growth factor receptor have been elucidated. Multiple therapeutic strategies that target the HER2/neu oncoprotein are under development. Trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA), a humanized monoclonal antibody that binds to the extracellular domain of the HER2/neu receptor, has undergone phase I, II, and III clinical trials. These studies have shown that, as a single agent, trastuzumab has substantial and reproducible antitumor activity in HER2/neu-amplified metastatic breast cancer. In addition, when added to chemotherapy, trastuzumab improves antitumor efficacy as measured by time to progression, response rate, and survival. Additional chemotherapy/trastuzumab combinations are under active evaluation, and new schedules of administration are being tested. Thus, trastuzumab is the first successful example of molecularly targeted therapy in the management of metastatic breast cancer.
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PMID:Overview of treatment results with trastuzumab (Herceptin) in metastatic breast cancer. 1177 5


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