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

Poly(DL-lactic acid) (PLA), poly(epsilon-caprolactone) (PCL), and their copolymers (PLA-CL) with various monomer compositions were synthesized, and their properties as matrix for the sustained release of drugs were evaluated. The copolymerization technique produced very soft films which incorporated the drugs without deterioration of the elastic properties. Cisplatin and MD-805 were loaded in the films by casting the polymer solution containing the drugs. Fractions of the drugs released from the PLA-CL films were governed by the initial loading, the film thickness, and the polymer molecular weight. The drug release profiles obeyed the classical Fickian diffusion equation at least in the early stage, but significant hydrolytic degradation of the matrix polymers occurred in the later stage, influencing the kinetics of drug release. The monomer composition of copolymer affected the release profile more strongly than the initial molecular weight of the copolymer.
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PMID:In vitro evaluation of sustained drug release from biodegradable elastomer. 179 48

Registered nurses (RNs) and clinical pharmacists in the Hematology-Oncology Clinic at Walter Reed Army Medical Center conducted a descriptive study to determine the effectiveness and safety of using indwelling peripheral intravenous catheters (pics) for daily administration of various chemotherapeutic agents given intermittently over a 3-5 day period to outpatients. Eighty-nine adult outpatients requiring daily doses of chemotherapy including Fluorouracil (5-FU) (Solopak, Elk Grove Village, IL), Leucovorin (Immunex, Seattle, WA), Cisplatin (CDDP) (Bristol-Meyers, Princeton, NJ), Etoposide (VP-16), (Gensia, Irving, CA), Topotecan (SmithKline Beecham, Philadelphia, PA), or Taxol (Mead Johnson, Princeton, NJ), plus antiemetics were studied. Vialon 20-, 22-, or 24-gauge indwelling PICs (Becton Dickinson, Sandy, UT), were placed. Approximately 80% of patients successfully completed treatment with the original PIC in place. Daily flushing of the PIC with 2 ml [corrected] of Heplock U100 (Elkins-Sinn, Cherry Hill, NJ), maintained Heplock patency.
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PMID:Use of an indwelling peripheral catheter for 3-5 day chemotherapy administration in the outpatient setting. 906 Mar 58

Genotoxic stress triggers signalling pathways that either mediate cell killing or protection of affected cells. While induction of p53 is observed for most of the genotoxins, activation of MAPK/SAPK cascades is not a general response. The role of MAPK/SAPK activation on cell fate, seems to be dependent, in some systems, on the balanced response among both cascades. We have here examined the effect of cis and trans-DDP on the activation of ERK and JNK activities. While no significant induction of ERK was observed with the compounds, both of them are able to strongly activate JNK. Trans-DDP response is rapid and transient while the cis-DDP one is slow and persistent. In contrast with the observed nuclear translocation of JNK in response to U.V. light, none of the platinum compounds induces translocation, on the contrary, activation of JNK occurs in both the nuclear and cytoplasmic compartments. Inhibition of tyrosine phosphatases by orthovanadate pretreatment prolongs the time of JNK induction in response to both platinum compounds. The positive modulation of JNK activation correlates with an increase in toxicity that, for cis-DDP corresponds to a tenfold decrease in the IC50. A strong increase in MKP-1 levels was observed only in response to trans-DDP suggesting the involvement of this activity in the downregulation of JNK activity in response to this compound. Altogether the results suggest that the prolonged activation of JNK in response to cis-DDP contributes to cell death induction.
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PMID:Cisplatin induces a persistent activation of JNK that is related to cell death. 948 43

Cisplatin (cis-diamminedichloroplatinum II), a potent antitumor compound, stimulates immune responses by activating monocytes/macrophages and other cells of the immune system. However, the mechanism by which cisplatin activates these cells is poorly characterised. Our earlier findings indicate that cisplatin treatment stimulates rapid tyrosine phosphorylation in a number of cellular proteins in murine macrophages. This initial tyrosine phosphorylation is an important regulatory mechanism and is followed by activation of several other proteins. In the present study, we report the involvement of other key molecules and the role of tyrosine phosphorylation in their activation in the signaling cascade of cisplatin. We observed the involvement of Ras (a low molecular weight GTP-binding protein) and ERK-1 (a MAP kinase) in this signaling cascade. Cisplatin treatment results in an increase in the expression of both Ras and ERK-1 in a dose-dependent manner, which was dependent upon tyrosine phosphorylation. Genistein a PTK inhibitor inhibited the cisplatin induced expression of Ras and ERK-1. These findings indicate that Ras and ERK-1 are important signaling molecules involved in the tumoricidal activation of macrophages with cisplatin and is dependent on initial tyrosine phosphorylation.
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PMID:Involvement of Ras and MAP kinase (ERK-1) in cisplatin-induced activation of murine bone marrow-derived macrophages. 967 53

Cisplatin treatment activates multiple signal transduction pathways, which can lead to several cellular responses including cell cycle arrest, DNA repair, survival, or apoptosis. We investigated the response of the mitogen-activated protein kinases, extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun-N-terminal kinase 1 (JNK1), and p38, to cisplatin treatment in the ovarian carcinoma cell line SK-OV-3. Cisplatin caused a late and prolonged induction in a dose-dependent manner of both ERK1/2 and JNK1 activity. ERK1/2 and JNK1 activities continued to increase in magnitude up to 24 h following initiation of cisplatin treatment. In contrast, cisplatin treatment had no effect on p38 activity. Transplatin failed to induce either ERK1/2 or JNK1 at 24 h, which suggests that the activation of these kinases was dependent on cisplatin-specific DNA damage. Treatment with cycloheximide resulted in inhibition of cisplatin-induced ERK1/2 activation, demonstrating that ERK1/2 activity induced by cisplatin was dependent on de novo protein synthesis. Furthermore, inhibition of cisplatin-induced ERK1/2 activity by PD 98059 caused enhanced cisplatin cytotoxicity. Similar enhanced cytotoxic effects of cisplatin were also observed following treatment with PD 98059 in the ovarian carcinoma cell line UCI 101. These observations indicate that ERK1/2 activation induced by cisplatin partially protects cells from cisplatin cytotoxicity. Continued investigation into the mechanism by which the ERK pathway and other signal transduction pathways modulate the response to cisplatin may be helpful in the development of new strategies for improving the therapeutic use of platinum drugs.
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PMID:Cisplatin-induced activation of mitogen-activated protein kinases in ovarian carcinoma cells: inhibition of extracellular signal-regulated kinase activity increases sensitivity to cisplatin. 1035 33

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

Interest in platinum compounds for the treatment of breast cancer has been reawakened because of preclinical studies indicating synergy of platinum salts with the monoclonal antibody trastuzumab in human breast cancer cell lines that overexpress HER2/neu. Cisplatin, carboplatin, and iproplatin are not very active as single agents in patients with previously treated metastatic breast cancer (MBC). The activity of oxaliplatin has not been adequately tested in refractory MBC. On the other hand, cisplatin is very active as first-line chemotherapy, with response rates (RR) of 50%; carboplatin appears to be moderately active in patients without prior chemotherapy (RR around 30%). The clinical effectiveness of the other platinum compounds (iproplatin, oxaliplatin, and others) has not yet been fully tested as first-line chemotherapy. Platinum compounds have been extensively tested in combination with other antitumoral agents. Cisplatin combinations have been employed as neoadjuvant chemotherapy in women with locally advanced breast cancer. These combinations are very active, although the precise contribution of cisplatin to the overall activity is not known. Combinations with cisplatin have been investigated, essentially, as salvage therapy for patients with previously treated MBC. The combinations of cisplatin with older pharmacological agents (5-fluorouracil, etoposide) have moderate activity, while the combinations of cisplatin with the newer agents (vinorelbine, paclitaxel, docetaxel, gemcitabine) appear to be more active. The combinations of carboplatin with the classical agents (5-fluorouracil, etoposide) are poorly active in previously treated MBC; however, the combination of carboplatin with the taxanes (docetaxel, paclitaxel) is more active. Of greatest interest is the synergy between the platinum derivatives and the monoclonal antibody trastuzumab demonstrated in vitro in breast cancer cell lines overexpressing HER2/neu. Currently, several combinations of platinum compounds (either cisplatin or carboplatin) with docetaxel and trastuzumab are under clinical testing in patients with MBC who overexpress HER2/neu. The preliminary results are very promising, and these combinations will soon be tested in the adjuvant setting. Cisplatin, carboplatin, and perhaps, oxaliplatin appear to have some antitumor activity in MBC and can be combined safely with other agents that are active in this disease. However, the precise role that platinum compounds play in the treatment of breast cancer remains to be defined.
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PMID:Platinum compounds in the treatment of advanced breast cancer. 1189 13

The constitutive activity of a number of growth and cell survival pathways are thought to contribute to the inherent resistance of melanoma to chemotherapy and radiotherapy. Many of these pathways are driven through the small GTPase Ras. Novel drugs such as the farnesyl transferase inhibitors (FTIs) and farnesyl thiosalicylic acid (FTS) interfere with the signaling of oncogenic Ras. The aim of our study was to assess the anti-tumour activity of the FTI SCH66336 in melanoma and to assess whether SCH66336 and FTS could modulate chemoresistance in melanoma cells. SCH66336 had marked anti-proliferative activity in both human and mouse melanoma cell lines, but not in non-transformed NIH 3T3 cells. The anti-proliferative activity of SCH66336 was due to G1-phase cell cycle arrest and retinoblastoma protein inactivation, followed by apoptosis. Cisplatin, when administered alone, induced little apoptosis. In combination with cisplatin, both FTS and SCH66336 markedly enhanced the level of cisplatin-induced apoptosis, an effect that was associated with enhanced G2/M cell cycle arrest. Pharmacological inhibitors of either ERK or PI-3 kinase/Akt did not mimic the chemosensitising activity of either SCH66336 or FTS. In summary, our study demonstrates that SCH66336 has good in vitro anti-tumour activity in both human and mouse melanoma cell lines, and suggests that Ras antagonists could be useful in overcoming chemoresistance to cisplatin in melanoma.
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PMID:Farnesyl transferase inhibitor SCH66336 is cytostatic, pro-apoptotic and enhances chemosensitivity to cisplatin in melanoma cells. 1267 74

cis-Diaminodichloroplatinum (II) (cisplatin) is one of the most effective anticancer drugs and is widely used for the treatment of squamous cell carcinoma (SCC). However, its efficacy is often limited due to the development of resistance. Although several factors implicated in cisplatin resistance have been identified, the resistance mechanisms in detail are not fully understood yet. In the present study, we have examined the implication of survival signaling pathways in cisplatin-resistance. Cisplatin induced activation of Ras and its downstream effector kinases, Raf/MEK/ERK in UM-SCC-23 human squamous cell carcinoma, suggesting that this anticancer drug activates survival signal pathway in addition to apoptosis signals. In cisplatin-resistant UM-SCC-23 in culture, which we have established, the protein levels of Ras, Raf-1 and MEK were drastically elevated compared to parent UM-SCC-23, and ERK and Akt signals were constitutively activated. U0126, an inhibitor for MEK and LY294002, an inhibitor for phosphatidylinositol 3-kinase (PI3K), sensitized resistant UM-SCC-23 to cisplatin-induced cell death. These results indicate that Raf/MEK/ERK and PI3K/Akt signal cascades may play a considerable role in cisplatin resistance in SCC.
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PMID:Cisplatin activates survival signals in UM-SCC-23 squamous cell carcinoma and these signal pathways are amplified in cisplatin-resistant squamous cell carcinoma. 1471 71

Surgery is the treatment of choice for major and minor salivary gland malignancies. Herein, the role of radiation and medical treatment in the multidisciplinary management of salivary gland tumours is discussed. Neutron irradiation and hyperfractionated external beam mega voltage irradiation improve local control. Combination of three dimensional conformal radiotherapy and intensive-modulated radiation therapy provide better local tumour delineation, better field design to encompass the tumour allowing dose escalation to target while sparing the surrounding normal tissue. Cisplatin-based chemotherapy provides a response rate > or = 45%, in a palliative setting. Concomitant chemo-radiotherapy could improve local control. Recent studies evaluated the expression of molecular targets in salivary gland carcinomas (c-kit = 53-90%, EGFR = 25-85%, c-erb-B2 = 11-58%, p53 = 11-67%, H ras = 18%); these targets are very important since new targeted drugs are now available. Anti-androgen therapy might have a role in the management of patients with ductal carcinoma. These new targeted drugs could be integrated with chemotherapy and radiotherapy in the treatment of locally advanced/metastatic salivary gland malignancies.
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PMID:Update and perspectives on non-surgical treatment of salivary gland malignancies. 1510 87


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