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)

New anticancer drugs with novel structures including paclitaxel, docetaxel, ilinotecan and gemcitabine have shown significant activity against various solid tumors in phase II trials. Phase II trials of combination regimens containing these drugs are currently in progress. Some combinations such as paclitaxel pluscisplatin in ovarian cancer have shown superiority over the past standard regimen. Not surprisingly, several analogues of these drugs have been developed and currently phase II trials are in progress. ET-743 may has some hope to become thefirst anticancer drug from a marine product. Oral chemotherapy is useful for treatment of outpatients. A combination regimen of UFT plus oral leucovorin has shown equivalent activity to 5-fluorouracil and leucovorin in advanced colorectal cancer, and capecitabine has shown superior activity and less toxicity than 5-fluorouracil and leucovorin in advanced colorectal cancer. Monoclonal antibody therapy has been successful in patients with breast cancer overexpressing HER2 and in patients with B-cell lymphoma. Currently clinical trials of 17-1A for colorectal cancer and HUM195 for acute myelogeneous leukemia are in progress. Recently presented results of angiogenesis inhibitors are discussed.
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PMID:Current Status and Perspectives in Cancer Chemotherapy. 1109 28

A mouse HER2-derived peptide, HER2p63 (A) (TYLPANASL), can induce K(d)-restricted mouse cytotoxic T lymphocytes (CTL) and also function as a tumor rejection antigen in an in vivo assay. Since the anchor motif of mouse K(d) for peptide binding has much similarity to that of human HLA-A2402, we asked if human HER2p63 (T) (TYLPTNASL) could induce HER2-specific CTL in HLA-A2402-positive individuals. Peripheral blood mononuclear cells (PBMC) of HLA-A2402-positive individuals were sensitized in vitro with HER2p63-pulsed autologous dendritic cells prepared from PBMC. CTL clone derived from these specifically lysed HER2-expressing cell lines bearing HLA-A2402. Cytotoxic activity of the CTL clone against the HER2-expressing cell line bearing HLA-A2402 was blocked by antibodies against CD3, CD8, HLA-A24 or MHC class I, and was also inhibited by the addition of excess HER2p63-pulsed C1R bearing HLA-A2402. Killer cells were generated from PBMC of seven healthy individuals and five ovarian cancer patients, all of HLA-A2402 type, by in vitro sensitization with HER2p63-pulsed autologous antigen presenting cells. These killer cells selectively lysed HER2-expressing SKOV3 transfected with HLA-A2402 cDNA, indicating high immunogenicity of HER2p63 in all 12 individuals examined.
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PMID:A novel human HER2-derived peptide homologous to the mouse K(d)-restricted tumor rejection antigen can induce HLA-A24-restricted cytotoxic T lymphocytes in ovarian cancer patients and healthy individuals. 1109 50

Functional significance has been demonstrated in vitro for the exon 3 T-->C Tyr113His amino acid substitution polymorphism of the microsomal epoxide hydrolase (EPHX) gene. The higher activity or fast TT genotype was previously reported to be associated with an increased risk of ovarian cancer, and this association may reflect enhanced activation of endogenous or exogenous substrates to more reactive and mutagenic derivatives. Components of cigarette smoke are examples of exogenous substrates subject to such bioactivation, and smoking exposure may thus modify the risk associated with the EPHX polymorphism. We examined 545 cases of epithelial ovarian cancer and 287 unaffected controls for this EPHX T-C genetic variant to investigate whether, in the Australian population, the TT genotype was associated with (i) specific ovarian tumor characteristics; (ii) risk of ovarian cancer, overall or for specific subgroups; and (iii) risk of ovarian cancer in smokers specifically. Genotyping was carried out using the Perkin-Elmer ABI Prism 7700 Sequence Detection System for fluorogenic polymerase chain reaction allelic discrimination. Stratification of the ovarian cancer cases according to tumor behavior (low malignant potential or invasive), grade, stage, and p53 immunohistochemical status failed to show any heterogeneity with respect to the genotype defined by the EPHX polymorphism. There was a suggestion of heterogeneity with respect to histologic subtype (P=0.03), largely due to a decreased frequency of the TT genotype in endometrioid tumors. EPHX genotype distribution did not differ significantly between unaffected controls and ovarian cancer cases (overall, low malignant potential, or invasive) either overall or after stratification by smoking status. However, the TT genotype was associated with a decreased risk of invasive ovarian cancer of the endometrioid subtype specifically (age-adjusted odds ratio=0.38, 95% confidence interval=0.17-0.87). The results suggest that the proposed EPHX-mediated bioactivation of components of cigarette smoke to mutagenic forms is unlikely to be involved in the etiology of ovarian cancer in general but that a greater rate of EPHX-mediated detoxification may decrease the risk of endometrioid ovarian cancer. Mol. Carcinog. 30:71-78, 2001.
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PMID:The microsomal epoxide hydrolase Tyr113His polymorphism: association with risk of ovarian cancer. 1125 66

The HER2 oncogene and its relative oncoprotein, gp185HER2, a transmembrane glycoprotein belonging to the epidermal growth factor receptor family, are overexpressed in a wide range of solid tumors including breast and ovarian cancer. In patients with breast cancer, both humoral and cell-mediated HER2 immune responses have been found as well as in some patients with gp185HER2 nonoverexpressing tumors. To establish whether peptide sequences identified as HLA-A2-restricted T-cell epitopes are expressed in breast tumor cell lines and tissues, we produced and characterized by different methodologic approaches polyclonal antibodies raised against four gp185HER2 peptides. Two of the antibodies recognized peptides eluted from the HLA-A2 groove of the mDAmB231 breast cancer cell line expressing a basal level of gp185HER2. Paraffin-embedded primary and metastatic breast tumors were specifically immunostained by all four reagents, thereby showing an overlapping reactivity. When this immunoreactivity was compared with that obtained using two different monoclonal antibodies, in 105 breast primary tumors and 36 corresponding lymph node metastases, we identified a subset of tumors that were negative with anti-gp185HER2 monoclonal antibodies and positive with the four antipeptide antibodies. Our novel observations provide in vivo evidence of the complexity involved in evaluating HER2 expression, and open a new path for understanding the biologic significance of HER2 status in breast tumors.
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PMID:Polyclonal antibodies against gp185HER2 peptides: their putative role in the identification of a particular HER2 status in patients with breast cancer. 1139 99

SUMMARY: The HER2 oncogene and its relative oncoprotein, gp185HER2, a transmembrane glycoprotein belonging to the epidermal growth factor receptor family, are overexpressed in a wide range of solid tumors including breast and ovarian cancer. In patients with breast cancer, both humoral and cell-mediated HER2 immune responses have been found as well as in some patients with gp185HER2 nonoverexpressing tumors. To establish whether peptide sequences identified as HLA-A2-restricted T-cell epitopes are expressed in breast tumor cell lines and tissues, we produced and characterized by different methodologic approaches polyclonal antibodies raised against four gp185HER2 peptides. Two of the antibodies recognized peptides eluted from the HLA-A2 groove of the mDAmB231 breast cancer cell line expressing a basal level of gp185HER2. Paraffin-embedded primary and metastatic breast tumors were specifically immunostained by all four reagents, thereby showing an overlapping reactivity. When this immunoreactivity was compared with that obtained using two different monoclonal antibodies, in 105 breast primary tumors and 36 corresponding lymph node metastases, we identified a subset of tumors that were negative with anti-gp185HER2 monoclonal antibodies and positive with the four antipeptide antibodies. Our novel observations provide in vivo evidence of the complexity involved in evaluating HER2 expression, and open a new path for understanding the biologic significance of HER2 status in breast tumors.
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PMID:Polyclonal Antibodies Against gp185HER2 Peptides: Their Putative Role in the Identification of a Particular HER2 Status in Patients With Breast Cancer. 1139 37

BRCA1 germline mutations have been linked to the development of hereditary breast and ovarian cancers. Recent studies suggest that BRCA1 may function in the regulation of basic cellular processes, including gene transcription, and sensing and/or repair of DNA damage. To further delineate the BRCA1 upstream and downstream steps involved in its role in the cellular response to ionizing radiation, we compared the effects of expression of an exogenous full-length Brca1 with those of a truncated Brca1 mutant in the ID-8 mouse ovarian cancer cell line after irradiation. We found that expression of both full-length and truncated Brca1 increased resistance to ionizing radiation. Expression of truncated, but not full-length, Brca1 then allowed us to identify new potential downstream targets of mutated BRCA1 like MAPK/ERK pathway members and also key genes involved in mutated BRCA1 signaling pathway response to ionizing radiation such as p53 and p21WAF1/CIP1. We therefore established an in vitro mouse model for studying the molecular effects of human BRCA1 germline mutations.
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PMID:Molecular pathways involved in response to ionizing radiation of ID-8 mouse ovarian cancer cells expressing exogenous full-length Brca1 or truncated Brca1 mutant. 1149 42

The cytotoxic activity of the imidazoacridinone C1311 was assessed on two ovarian cancer cell lines (A2780, OAW42) and one osteogenic sarcoma cell line (U2-OS) and their sublines (A2780Cp8, OAW42-MER and U2-OS-R) with experimentally induced resistance to cisplatin. A 1-h exposure to C1311 significantly inhibited the growth of all cell lines, with IC50 values ranging from 0.50 +/-0.11 to 4.10+/-0.36 microM. No or only partial cross-resistance was found between C1311 and cisplatin in the different cell lines. Treatment with equitoxic (IC50) C1311 concentrations consistently induced accumulation of cells in the G2M phase. The cyclin B1-associated p34(cdc2) kinase activity in cells arrested in G2M was superimposable to that of control cells in the OAW42-MER and U2-OS cell lines, whereas a reduction of cdc2 catalytic activity was observed in OAW42 and U2-OS-R cells. Exposure to C1311 (IC50) induced apoptosis in the U2-OS and U2-OS-R cell lines, whereas in the OAW42 and OAW42-MER cell lines there was a negligible percentage of apoptotic cells. In U2-OS, U2-OS-R and OAW42 cells, C1311 induced an increase in p53 expression and an increase in p21waf1 protein, whereas p53 failed to transactivate p21waf1 in OAW42-MER cells. An almost complete abrogation of bcl-2 was observed in U2-OS-R cells in correspondence with the peak of apoptosis induction. Our results indicate that C1311 is active against human ovarian cancer and osteogenic sarcoma cells and is not cross-resistant with CDDP. Moreover, C1311 blocks cells in the G2M phase and induces apoptosis in a small percentage of osteogenic sarcoma cells.
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PMID:Cell growth inhibition, G2M cell cycle arrest and apoptosis induced by the imidazoacridinone C1311 in human tumour cell lines. 1157 53

A human ovarian carcinoma cell line (UCI-107) was genetically engineered to secrete the cytokine granulocyte-macrophage colony stimulating factor (GM-CSF), by retroviral medicated gene transduction. This line was transduced with the LXSN retroviral vector containing the human GM-CSF gene and the neomycin resistance selection marker. Numerous GM-CSF secreting clones were randomly isolated and one clone, termed UCI-107M GM-CSF-MPS, extensively characterized. This clone was shown to constitutively secrete high levels of GM-CSF (ie 420-585 pg ml-1 105 cells-1 48 h-1 for over 35 passages and 6 months of study. Like the parental cell line UCI-107, UCI-107M GM-CSF-MPS cells expressed MHC class I and Her2/Neu surface antigens but did not express detectable MHC class II, ICAM-1 or CA-125. No change in the expression of these surface proteins was noted between the parental cells and this GM-CSF secreting clone. The morphology of UCI-107M GM-CSF-MPS did not differ from that of the parental or LXSN vector control cells; however, parental cells had a slightly faster growth rate than the transductants. UCI-107M GM-CSF-MPS was sensitive to gamma irradiation, since as little as 2500 rads killed the cells within 10 days of irradiation. However, even after higher doses of irradiation (ie 10000 rads), GM-CSF secretion continued in vitro until about day 8. Interestingly, irradiation induced up-regulation of the surface antigens previously expressed, and they remained up-regulated for as long as the cells remained viable. The potential use of these GM-CSF secreting ovarian carcinoma cells as vaccines for women with advanced ovarian cancer will be discussed.
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PMID:Development and in vitro characterization of a GM-CSF secreting human ovarian carcinoma tumor vaccine. 1157 12

Overexpression of the HER2/neu oncogene is a frequent molecular event in multiple human cancers including breast and ovarian cancer. Patients with breast cancer that overexpress HER2/neu have a poor prognosis, shorter relapse time, and low survival rate. In this report, the biologic signaling pathway mediated by HER2/neu tyrosine kinase receptor will be discussed. The mechanisms leading to transformation and tumorigenesis of HER2/neu-overexpressing cells will also be addressed. 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. In this report we will summarize strategies for targeting the HER2/neu gene, including targeting the gene product p185 oncoprotein, or transcriptional downregulation through the oncogene promoter. These fundamental studies, performed by different groups, warrant the clinical potential of targeting HER2/neu in cancer therapy.
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PMID:HER2 overexpression and cancer targeting. 1170 3

During the past decade there has been renewed interest in the use of vaccine immunotherapy for the treatment of cancer. This review focuses on HER2/neu, a tumour-associated antigen that is overexpressed in 10-40% of breast cancers and other carcinomata. Several immunogenic HER2/neu peptides recognized by T lymphocytes have been identified to be included in cancer vaccines. Some of these peptides have been assessed in clinical trials of patients with breast and ovarian cancer. Although it has been possible to detect immunological responses against the peptides in the immunized patients, no clinical responses have so far been described. Immunological tolerance to self-antigens like HER2/neu may limit the functional immune responses against them. It will be of interest to determine whether immune responses against HER2/neu epitopes can be of relevance to cancer treatment.
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PMID:Update on HER-2 as a target for cancer therapy: HER2/neu peptides as tumour vaccines for T cell recognition. 1173 93


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