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

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Preclinical data indicate that trastuzumab (Herceptin) has the potential for synergistic or additive effects in combination with therapies including chemotherapy and hormonal agents, providing the rationale for a number of clinical trials in women with HER2-positive metastatic breast cancer. A recently reported phase II trial has demonstrated that trastuzumab plus vinorelbine is both effective (overall response rate 75%) and well tolerated, with the major side effects being typical of single-agent vinorelbine. Other combinations of trastuzumab with a variety of other chemotherapeutic and hormonal agents are also being assessed. In an effort to overcome the cardiotoxicity observed with trastuzumab plus doxorubicin in the pivotal phase III trial, combination regimens involving potentially less toxic anthracyclines such as epirubicin and liposomal formulations of doxorubicin are ongoing. In addition, trials are investigating whether trastuzumab can reverse the resistance to hormonal therapy that develops in most women with metastatic breast cancer. These and other studies will identify the regimens that produce the best outcomes with the fewest possible side effects in women with HER2-positive breast cancer.
...
PMID:New combinations with Herceptin in metastatic breast cancer. 1169 88

The taxanes and Herceptin have been shown to possess significant clinical activity in metastatic breast cancer. Preclinical testing of taxane/Herceptin combinations demonstrated additive and synergistic interactions with paclitaxel and docetaxel, respectively. In a pivotal clinical trial, combination of paclitaxel (3-weekly) and Herceptin was associated with an increased response rate compared with paclitaxel monotherapy (41% vs. 17%; p = 0.001). The combination therapy also significantly improved time to disease progression (6.9 vs. 2.7 months; p < 0.05). In a phase II study of weekly paclitaxel plus Herceptin in patients with normal or increased tumor HER2 levels, a response was observed in 60% of patients and the regimen was well tolerated. Responses were more frequent in patients with HER2-overexpressing tumors (83% vs. 45%). Preliminary results from a phase II study of Herceptin plus docetaxel in patients with HER2-overexpressing tumors indicate significant activity, with a response observed in 7 (44%) of 16 evaluable patients. The preliminary results of a trial of weekly docetaxel and Herceptin demonstrate a response rate of 54% in 13 evaluable patients. Additional European trials of Hercep- tin/taxane combinations as first- and second-line and adjuvant therapy are ongoing. The results of the studies to date indicate that regimens combining Herceptin with 3-weekly and weekly taxane are effective and well tolerated.
...
PMID:Interaction between Herceptin and taxanes. 1169 87

Approximately 25,000 patients have been treated to date with the humanized anti-HER2 monoclonal antibody, Herceptin. This therapy has proved effective and well tolerated in patients with HER2-positive metastatic breast cancer; adverse events were generally infusion-related fever and chills of mild-to-moderate severity. Cardiotoxicity and infusion-related reactions emerged as the two main safety concerns with the use of Herceptin. Retrospective analysis revealed a higher incidence of heart failure when Herceptin was combined with anthracyclines than that expected with anthracyclines alone. Age, anthracycline exposure and cardiac risk factors were found to be predictors of cardiac adverse events. Patients experiencing cardiac dysfunction responded well to standard cardiac medication and the majority improved. Cardiac function should be monitored regularly and Herceptin should be discontinued if significant heart failure develops unless the benefits for an individual patient outweigh the risks. Of 25,000 patients, 74 (0.3%) were reported to have experienced a serious infusion-related reaction. The majority occurred during or shortly after the first infusion and were characterized by respiratory symptoms. Most patients were successfully treated; a total of 33 patients continued Herceptin therapy with no recurrence of infusion reactions. Although the benefit to risk ratio of Herceptin remains favorable, physicians must be vigilant and aggressive in managing cardiotoxicity and infusion-related reactions.
...
PMID:Retrospective analysis of the safety of Herceptin immunotherapy in metastatic breast cancer. 1169 89

Measurement of molecular markers predictive of response to therapy should enable more selective and effective utilization of anticancer agents. The predictive value of HER2 remains a complex and inconclusive subject. In metastatic breast cancer, HER2-positive, ER-positive patients can show responses to endocrine treatment, but experience shorter time to progression and survival than HER2-negative patients. In the adjuvant setting, weak, retrospective evidence suggests that tamoxifen is potentially harmful in HER2-positive patients and that there is no benefit from prolonged tamoxifen therapy. It has not yet been demonstrated conclusively that HER2 positivity increases resistance to adjuvant cyclophosphamide, methotrexate, 5-FU (CMF), but there are indications that HER2-positive patients benefit more from adequately dosed anthracyclines than from CMF. The greatest value of HER2 as a predictive marker lies in the prediction of response to therapies that target HER2, such as Herceptin. Patients with strongly HER2-positive breast cancer derive significant clinical benefit from single-agent and combined Herceptin therapy. HER2 testing has become an integral part of the optimal management of the breast cancer patient. Best current practice in adjuvant breast cancer therapy based on the current knowledge of the potential predictive power of HER2 constitutes not denying tamoxifen to HER2-positive, ER-positive patients or CMF to HER2-positive patients. Outside of clinical trials, adequately dosed anthracycline-based chemotherapy is the current preferred adjuvant treatment option for HER2-positive patients.
...
PMID:The predictive value of HER2 in breast cancer. 1169 91

Clinical trials using the humanized version of the anti-HER2 murine monoclonal antibody 4D5, trastuzumab, have shown antitumor activity in patients with HER2-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 with the same chemotherapy alone. Because of the promising safety and efficacy profile of trastuzumab in the metastatic setting, this novel biologic has now entered adjuvant breast cancer trials in both the United States and Europe. Five clinical trials are discussed in this report, capturing the evolving role of trastuzumab as adjuvant therapy for breast cancer.
...
PMID:Integration of trastuzumab into adjuvant systemic therapy of breast cancer: ongoing and planned clinical trials. 1170 95

Data from phase III clinical trials suggest that high dose chemotherapy (HDC) is currently not indicated for any stage of breast cancer. Therefore HDC should only be considered within the context of clinical trials. Furthermore, there is no significant evidence to support the routine use of taxanes in women with metastatic breast cancer (MBC) and further research is required to address this issue. A well-designed randomised controlled trial has shown that expressive support psychosocial therapy does not improve survival of women with MBC. Her2 overexpression seems to be a significant predictor of response to taxanes and anthracyclines, and FISH testing for Her2 seems to be superior to IHC in predicting response to Herceptin. Recent evidence confirms the independent prognostic value of VEGF, UPA and PAI-1 in women with early breast cancer and suggests that such parameters may have a role in selecting systemic therapy. Biological therapy using inhibitors/antagonists of angiogenesis and EGFR seems to be safe and well tolerated. Although the response rates are currently unimpressive, further research using survival as an endpoint is required.
...
PMID:Recent advances in breast cancer (the 37th ASCO meeting, May 2001). 1175 80

The HER2 protein is encoded by the HER2/neu gene and it is homologous to the epidermal growth factor receptor. Overexpression of HER2, usually in association with gene amplification, occurs in approximately 25-30% of breast cancers. There are currently several different methods available to evaluate HER2 status, e.g. immunohistochemical (IHC), and fluorescence in situ hybridization (FISH) assays. The HER2 protein is a viable therapeutic target. The humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin) has demonstrated activity in clinical trials in women with metastatic breast cancer overexpressing HER2. The mechanisms of the action of this antibody involve disruption of DNA repair and induction of antibody-dependent cellular cytotoxicity. Response rates to the antibody given as a single agents in the treatment of HER2 overexpressing metastatic breast cancer have ranged from 12 to 27%. Patients who received trastuzumab in combination with chemotherapy had a significantly longer time to progression, higher overall survival compared with patients who had received chemotherapy alone. In the treatment of women with HER2 overexpressing tumors an overall response rate of 57% for combination trastuzumab plus paclitaxel compared with 25% for paclitaxel alone was found. Trastuzumab has an important role in the treatment of HER2 overexpressing metastatic breast cancer. Its place in adjuvant treatment has not been proved up to now. The optimal use of trastuzumab in the treatment of HER2 positive advanced breast cancer is under active investigation. Due to the high rate of clinical activity and low incidence of severe toxicity trastuzumab is a very promising drug in the treatment of breast cancer. The author's purpose was to summarize the results of the trials using trastuzumab treatment, and discuss the methods used to determine the HER2 status.
...
PMID:[Human recombinant anti-HER2 monoclonal antibody--a new targeted treatment in breast cancer]. 1177 Jan 75

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.
...
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.
...
PMID:Overview of treatment results with trastuzumab (Herceptin) in metastatic breast cancer. 1177 5

(1) In the absence of a reference treatment, patients with metastatic breast cancer qualifying for cytotoxic chemotherapy are generally treated with the doxorubicin + cyclophosphamide combination. (2) Trastuzumab, a monoclonal antibody directed against HER2 protein, has been granted marketing authorisation for the treatment of metastatic breast cancer in women with high HER2 protein levels, either as third-line monotherapy, or as first-line combination therapy with paclitaxel. (3) The clinical file only comprises two trials, the results of which are difficult to interpret. (4) In second- or third-line monotherapy, the only available trial (a non comparative study involving 222 patients) gave a median survival time of 13 months. For want of comparative data, there is no way of knowing if the clinical benefit and adverse effects profile of trastuzumab are better than those of other cytotoxic agents. (5) In first- or second-line treatment, there is only one unblinded comparative trial: it compared four groups receiving anthracycline + cyclophosphamide + trastuzumab; anthracycline + cyclophosphamide; paclitaxel + trastuzumab; or paclitaxel alone. The addition of trastuzumab appeared to extend the median survival time by 4-5 months. (6) The main known risks of trastuzumab therapy are cardiac reactions (the most severe) and flu-like syndromes (the most frequent, occurring in 40% of patients). (7) In the two available trials, a retrospective analysis suggested that the impact of trastuzumab was related to the amount of HER2 protein in the tumour. Unfortunately, HER2 assays are poorly standardised. Approximately one-quarter of patients appear to have high tumour HER2 protein contents. (8) At the time of writing (May 2001), the treatment of metastatic breast cancer is not modified by the advent of trastuzumab.
...
PMID:Trastuzumab: new preparation. May help some patients with breast cancer, but too many unknowns. 1178 63


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---