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)

Overexpression of the HER2/neu oncogene and receptor protein has been reported in 20%-30% of patients with breast cancer and is associated with a poor prognosis. HER2/neu expression in breast cancer patients assessed by fluorescence in situ hybridization or immunohistochemistry is a predictor for response to trastuzumab, a humanized monoclonal antibody against the HER2/neu cell-surface protein. Data regarding HER2/neu expression in lung cancer are more limited, and there is little information regarding HER2/neu expression and response to trastuzumab alone or in combination with chemotherapeutic agents. Gemcitabine is an active agent against non-small-cell lung cancer (NSCLC) and has demonstrated activity in breast cancer as well. In vitro modified tetrazolium salt growth assays were performed to determine whether the combination of trastuzumab/gemcitabine produced synergistic or additive effects on breast and lung cancer cell lines. The effects of trastuzumab alone, gemcitabine alone, and the trastuzumab/gemcitabine combination was evaluated on 4 NSCLC cell lines, 1 small-cell lung cancer (SCLC) cell line, and 2 breast cancer cell lines. HER2/neu surface protein expression was assessed by fluorescence flow cytometry and immunohistochemistry. Fluorescence in situ hybridization analysis was used to study gene expression. Trastuzumab treatment alone resulted in growth inhibition in all cell lines expressing HER2/neu and the inhibitive effect correlated with the level of cell surface HER2/neu protein expression. Treatment with gemcitabine alone resulted in growth inhibition in both breast and NSCLC cell lines. A synergistic growth inhibition effect was seen with the trastuzumab/ gemcitabine combination as indicated by combination index values < 1. The degree of synergy observed did not directly correlate with the level of surface protein expression, as synergy was seen even in cancer cell lines expressing low levels of HER2/neu. No treatment effect was seen in the SCLC cell line, which did not express HER2/neu. These preclinical studies indicate a need to study the clinical synergistic effects of the gemcitabine/trastuzumab combination in breast cancer and NSCLC patients whose tumors overexpress HER2/ neu.
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PMID:Preclinical studies of gemcitabine and trastuzumab in breast and lung cancer cell lines. 1205 39

The background, rationale, and preliminary results of a phase II trial of gemcitabine plus trastuzumab in heavily pretreated metastatic breast cancer patients are presented. Gemcitabine and trastuzumab both exhibit single-agent activity in previously treated metastatic breast cancer. Preclinical studies of gemcitabine and trastuzumab in combination showed additive or synergistic antitumor effects in human breast cancer cell lines that overexpress HER2. A multicenter phase II trial was thus conducted to define the safety and efficacy of gemcitabine/trastuzumab in patients previously treated for metastatic breast cancer. Women with measurable metastatic breast cancer whose primary or secondary tumor overexpressed HER2 were eligible for inclusion. Gemcitabine 1,200 mg/m(2) was administered on days 1 and 8 of a 21-day cycle. Trastuzumab was administered at a loading dose of 4 mg/kg initially, then at 2 mg/kg weekly thereafter. Preliminary analysis of 38 evaluable patients showed that gemcitabine/trastuzumab was well tolerated and had significant antitumor activity in this patient population. The study is now concluded, and final analysis of the data is nearing completion. Publication of the results is anticipated in 2003.
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PMID:Gemcitabine and trastuzumab in metastatic breast cancer. 1272 22

Gemcitabine (Gemzar) and paclitaxel show good activity as single agents and combined in metastatic breast cancer, and the combination of paclitaxel/trastuzumab (Herceptin) has been shown to prolong time to disease progression and survival significantly in this setting. Preclinical data indicate additive or synergistic effects of gemcitabine and trastuzumab in HER2-positive human breast cancer cell lines. In a phase II trial, patients with HER2-overexpressing metastatic breast cancer who had received no prior chemotherapy for metastatic disease received gemcitabine at 1,200 mg/m2 on days 1 and 8 and paclitaxel at 175 mg/m2 on day 1 every 21 days for six cycles plus trastuzumab at an initial loading dose of 4 mg/kg followed by 2 mg/kg weekly; patients without progressive disease after six cycles continued to receive trastuzumab until disease progression. Overall, objective response was observed in 28 (67%) of 42 evaluable patients, including complete response in 4 (10%) and partial response in 24 (57%); stable disease was observed in 7 (17%) and progressive disease was observed in 6 (14%). Median time to treatment failure was 9+ months. Median overall survival has not yet been reached, but is estimated at approximately 27 months. Significant toxicities apart from neutropenia were uncommon. The triplet combination of gemcitabine, paclitaxel, and trastuzumab is highly active and well tolerated in patients with HER2-overexpressing metastatic breast cancer.
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PMID:Gemcitabine, paclitaxel, and trastuzumab in metastatic breast cancer. 1476 3

In this study, we investigated the involvement of Akt and members of the mitogen-activated protein kinase (MAPK) superfamily, including ERK, JNK, and p38 MAPK, in gemcitabine-induced cytotoxicity in human pancreatic cancer cells. We found that gemcitabine induces apoptosis in PK-1 and PCI-43 human pancreatic cancer cell lines. Gemcitabine specifically activated p38 MAPK in a dose- and time-dependent manner. A selective p38 MAPK inhibitor, SB203580, significantly inhibited gemcitabine-induced apoptosis in both cell lines, suggesting that phosphorylation of p38 MAPK may play a key role in gemcitabine-induced apoptosis in pancreatic cancer cells. A selective JNK inhibitor, SP600125, failed to inhibit gemcitabine-induced apoptosis in both cell lines. MKK3/6, an upstream activator of p38 MAPK, was phosphorylated by gemcitabine, indicating that the MKK3/6-p38 MAPK signaling pathway is indeed involved in gemcitabine-induced apoptosis. Furthermore, gemcitabine-induced cleavage of the caspase substrate poly(ADP-ribose) polymerase was inhibited by pretreatment with SB203580, suggesting that activation of p38 MAPK by gemcitabine induces apoptosis through caspase signaling. These results together suggest that gemcitabine-induced apoptosis in human pancreatic cancer cells is mediated by the MKK3/6-p38 MAPK-caspase signaling pathway. Further, these results lead us to suggest that p38 MAPK should be investigated as a novel molecular target for human pancreatic cancer therapies.
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PMID:Involvement of p38 mitogen-activated protein kinase in gemcitabine-induced apoptosis in human pancreatic cancer cells. 1500 13

The HER2/neu oncogene is overexpressed in up to 70% of human pancreatic cancer specimens when compared to normal pancreatic tissue. This cell surface receptor can be targeted specifically by the neutralizing antibody Herceptin. Herceptin has been successfully used in combination with other chemotherapeutic agents in breast cancer, a cancer in which only 30% of patients harbor elevated HER2/neu levels. In the present study, we investigated the therapeutic efficacy of Herceptin in combination with gemcitabine and docetaxel. Gemcitabine is currently the standard chemotherapeutic agent used to treat pancreatic cancer. In contrast, docetaxel, a taxane, is only just being investigated in pancreatic cancer. Tumor cell resistance to taxanes is at least in part mediated by the HER2/NEU oncogene. We have previously characterized HER2/NEU expression in human pancreatic cancer cell lines and studied the anti-tumor activity of Herceptin monotherapy in vitro and in vivo. In the present study, combination therapy resulted in a dramatic improvement of animals bearing human pancreatic cancer xenografts. Furthermore, metastasis and production of ascites was lower when a combination of these three agents was used. We conclude that, as with breast cancer, the anti-tumor activity of Herceptin may be improved by combination with taxanes or gemcitabine.
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PMID:Combination therapy for advanced pancreatic cancer using Herceptin plus chemotherapy. 1614 31

Management of metastatic breast cancer (MBC) is difficult and overall response rates (ORR) resulting from anthracycline and taxane-based regimens remain modest. The antimetabolite drug gemcitabine has been shown to have high activity when used as first-line treatment of MBC, particularly when incorporated into combined therapy regimens. Gemcitabine-containing regimens have also been used successfully as salvage therapy in women with anthracycline or taxane-pretreated MBC. Phase II clinical studies have demonstrated high ORR with gemcitabine-docetaxel (ORR: 36-65.5%) and gemcitabine-paclitaxel (ORR: 40-68%) combination regimens. A highly favourable risk-benefit ratio has also been reported for gemcitabine-containing triplets such as gemcitabine-paclitaxel-epirubicin (ORR: 92%) and gemcitabine-paclitaxel-doxorubicin (ORR: 80.4%). Gemcitabine-containing regimens have a favourable toxicity profile with few serious toxic events reported. An important step forward in the evaluation of novel chemotherapeutic regimes for MBC is establishing a correlation between disease markers and response to therapy. Preliminary data suggest that there is a close relationship between HER2 extracellular domain levels (>30 ng/ml) and treatment outcome. HER2-positive patients had a lower ORR to gemcitabine-paclitaxel chemotherapy than women who were HER2-negative. Further studies to establish a link between other breast cancer markers and predicted response to treatment are warranted.
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PMID:Gemcitabine-taxane experience in the treatment of metastatic breast cancer. 1636 May 42

Anthracyclines and the taxanes are now used earlier in the course of therapy for metastatic breast cancer, and increasingly as part of adjuvant treatment. Accordingly, novel therapies are warranted, including alternatives to anthracyclines and combination strategies in the setting of disease resistance to or disease progression after anthracycline and taxane therapy. Gemcitabine is part of this strategy. The gemcitabine/paclitaxel combination has emerged as part of a new standard of combination therapy for advanced breast cancer, based on phase III data showing superiority of this combination over paclitaxel alone in the first-line therapy setting. Gemcitabine alone, or in combination with paclitaxel and other agents, is also undergoing evaluation in other settings including the refractory metastatic setting, as part of management of patients with HER2-positive disease, and also as part of adjuvant therapy for breast cancer.
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PMID:Role of gemcitabine in breast cancer management: an update. 1647 12

Pancreatic cancer (PCa) is one of the most lethal malignancies in humans. Gemcitabine is the current standard chemotherapy of advanced PCa but it is still far from optimal and novel therapeutic strategies are urgently needed. For the near future, tyrosine kinase inhibitors (TKIs) hold great promise as a therapeutic strategy. Tyrosine kinases (TKs) play a pivotal role in intercellular signal transduction and regulate crucial processes of tumor cells such as proliferation, migration, survival and angiogenesis. Several TKs--such as EGFR, VEGFR, PDGFR and Src--are known to be overexpressed or constitutively activated in PCa. Hence, blocking receptor tyrosine kinases (RTKs) and non-receptor, cytoplasmic tyrosine kinases (CTKs) represents a rational approach to treat PCa. In particular, cetuximab and erlotinib, the monoclonal antibodies against EGFR-1 (ErbB-1) showed promising activity in Phase II and Phase III trials and their combination with gemcitabine resulted in synergistic antitumor activity. In addition, small antiangiogenic molecules such as VEGFR-2 inhibitors, PDGFR inhibitors and multiple receptor targeting agents are under active investigation. Association of chemoresistance with the activity of certain tyrosine kinases (e.g. ErbB-1 and Src) has been described for pancreatic cancer and makes a strong case for combining gemcitabine with TKIs. Combinations of different TKIs might also be used to target the cancer cell micro-environment. Detailed molecular characterization of tumor cells and combinations of appropriate TKIs with cytotoxic agents such as gemcitabine are expected to lead to improved therapy of pancreatic cancer.
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PMID:Tyrosine kinase inhibitors and gemcitabine: new treatment options in pancreatic cancer? 1662 76

Purpose. To assess the toxicity and efficacy of biweekly gemcitabine plus vinorelbine in first-line advanced breast cancer, and to establish whether circulating HER2 ECD levels correlate with the efficacy of the combination. Patients and methods. 52 patients were treated with gemcitabine 2500 mg/m(2) plus vinorelbine 30 mg/m(2), both on day 1 of 14-day cycles, for a maximum of 10 cycles. Baseline serum levels of HER2 ECD were assessed with an ELISA. Results. All patients were evaluable for toxicity, and 50 for efficacy. Overall toxicity was moderate. Grade 3 neutropenia occurred in 35% of patients and grade 4 in 19%. Other grade 3 toxicities were observed in less than 6%. There was one episode of febrile neutropenia, and one death after cycle three. Overall response rate was 52% (95% CI: 38% to 66%), with 2 patients achieving a CR (4%). Response rate did not correlate with HER2 ECD, with 50% of HER2 ECD positive patients responding, vs 48.5% of the HER2 ECD negative. Median overall survival was 24.6 months. Conclusion. Gemcitabine plus vinorelbine, given as an every-two-week schedule, is an active regimen in advanced breast carcinoma. This combination can be an option when anthracyclines and taxanes are not preferred. HER2 ECD has no predictive value in this non-taxane combination.
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PMID:Biweekly gemcitabine plus vinorelbine in first-line metastatic breast cancer: efficacy and correlation with HER2 extracellular domain. 1716 63

Breast cancer is the most common malignancy in women worldwide, and represents the leading cause of death in the female population. Incidence of breast cancer increases with age, and older patients are more likely to have disseminated disease at diagnosis. For those patients who relapse after endocrine treatment or in which the tumor does not express hormone receptors, chemotherapy should be considered. Single agent sequential regimens should be preferred to combination regimens, which are usually more toxic and provide a limited survival gain. New drugs which have proven efficacy against metastatic breast cancer are Taxanes (Paclitaxel and Docetaxel), Vinorelbine, Capecitabine, Gemcitabine, various and newer formulations of Anthracyclines (Epirubicin, oral Idarubicin, liposomal Doxorubicin). The anti-HER2 monoclonal antibody Trastuzumab in association with chemotherapy can be administered to elderly patients who present with HER2 overexpressing tumors, though cardiac monitoring is necessary due to cardiac adverse events. Bevacizumab, an anti-VEGF monoclonal antibody, was recently patented and approved in combination with Paclitaxel for the treatment of metastatic breast cancer. Globally, there is need to develop therapeutics able to circumvent resistance against hormonal and other therapies for advanced breast cancer, which are expected to be safe and effective in this age class.
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PMID:Chemotherapy and targeted agents for elderly women with advanced breast cancer. 1899 87


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