Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human ovarian carcinoma cell lines were genetically engineered to secrete the cytokine interleukin-4 (IL-4) by retroviral-mediated gene transduction. These cells were transduced with the LXSN retroviral vector containing the human IL-4 gene and the neomycin resistance selection marker. Numerous IL-4-secreting clones were isolated from different papillary serous carcinoma cell lines, including SKOV-3, UCI-101, and UCI-107, and one clone derived from UCI-107 extensively characterized. This clone, termed UCI 107E IL-4 GS, was shown to constitutively express high levels of IL-4 (i.e., 900 to 1300 pg/ml/10(5) cells/48 hr) for over 35 passages and 6 months of study. Like the parental cell line (UCI-107), UCI 107E IL-4 GS cells expressed MHC class I and Her-2/neu surface antigens but did not express detectable MHC class II, ICAM 1, CA 125, or IL-4 receptors. No increase in expression of surface proteins was noted between parental and UCI 107E IL-4 GS. The morphology of this clone did not differ from that of the parental or LXSN vector control cells; however, parental cells had a faster growth rates than transductants. UCI 107E IL-4 GS was sensitive to gamma irradiation since as little as 2500 rad killed most of the cells within 10 days of irradiation. However, after irradiation, IL-4 secretion continued until about Day 8. The potential use of these IL-4-secreting ovarian carcinoma cells as vaccines for woman with advanced ovarian cancer will be discussed.
 ...
PMID:Development and characterization of an IL-4-secreting human ovarian carcinoma cell line. 762 10

Dendritic cells (DCs) are bone marrow-derived leukocytes that function as potent antigen presenting cells capable of initiating T cell-dependent responses from quiescent lymphocytes. DC pulsed with tumor-associated antigen (TAA) peptide or protein have recently been demonstrated to elicit antigen-specific protective antitumor immunity in a number of murine models. Transduction of DCs with TAA genes may allow stable, prolonged antigen expression as well as the potential for presentation of multiple, or unidentified, epitopes in association with major histocompatibility complex class I and/or class II molecules. To evaluate the potential efficacy of retrovirally transduced DCs, bone marrow cells harvested from BALB/c mice were transduced with either a model antigen gene encoding beta-galactosidase (beta-gal) or a control gene encoding rat HER-2/neu (Neu) by coculture with irradiated ecotropic retroviral producer lines. Bone marrow cells were differentiated into DC in vitro using granulocyte/macrophage colony-stimulating factor and interleukin-4. After 7 d in culture, cells were 45-78% double positive for DC phenotypic cell surface markers by FACS(R) analysis, and DC transduced with beta-gal were 41-72% positive for beta-gal expression by X-gal staining. In addition, coculture of beta-gal transduced DC with a beta-gal-specific T cell line (CTLx) resulted in the production of large amounts of interferon-gamma, demonstrating that transduced DCs could process and present endogenously expressed beta-gal. DC transduced with beta-gal and control rat HER-2/neu were then used to treat 3-d lung metastases in mice bearing an experimental murine tumor CT26.CL25, expressing the model antigen, beta-gal. Treatment with beta-gal-transduced DC significantly reduced the number of pulmonary metastatic nodules compared with treatment with Hank's balanced salt solution or DCs transduced with rat HER-2/neu. In addition, immunization with beta-gal-transduced DCs resulted in the generation of antigen-specific cytotoxic T lymphocytes (CTLs), which were significantly more reactive against relevant tumor targets than CTLs generated from mice immunized with DCs pulsed with the Ld-restricted beta-gal peptide. The results observed in this rapidly lethal tumor model suggest that DCs transduced with TAA may be a useful treatment modality in tumor immunotherapy.
 ...
PMID:Dendritic cells retrovirally transduced with a model antigen gene are therapeutically effective against established pulmonary metastases. 933 60

Sialidase (neuraminidase), encoded by the neu-1 gene in the major histocompatibility complex locus catalyzes the intralysosomal degradation of sialylated glycoconjugates. Inherited deficiency of sialidase results in sialidosis or galactosialidosis, both severe metabolic disorders associated with lysosomal storage of oligosaccharides and glycopeptides. Sialidase also plays an important role in cellular signaling and is specifically required for the production of cytokine interleukin-4 by activated T lymphocytes. In these cells, neu-1-encoded sialidase activity is increased on the cell surface, suggesting that a specific mechanism regulates sorting of this enzyme to the plasma membrane. We investigated that mechanism by first showing that sialidase contains the internalization signal found in lysosomal membrane proteins targeted to endosomes via clathrin-coated pits. The signal consists of a C-terminal tetrapeptide (412)YGTL(415), with Tyr(412) and Leu(415) essential for endocytosis of the enzyme. We further demonstrated that redistribution of sialidase from lysosomes to the cell surface of activated lymphocytes is accompanied by increased reactivity of the enzyme with anti-phosphotyrosine antibodies. We speculate that phosphorylation of Tyr(412) results in inhibition of sialidase internalization in activated lymphocytes.
 ...
PMID:Intracellular distribution of lysosomal sialidase is controlled by the internalization signal in its cytoplasmic tail. 1157 Dec 82

The therapeutic efficacy of HER2/c-erbB-2/neu DNA immunization on mouse tumor cells expressing exogenous human or rat p185neu but not on mouse tumor cells naturally expressing mouse p185neu has been demonstrated. We investigated the feasibility of using N-terminal rat neu DNA immunization on mouse tumor overexpressing endogenous p185neu and enhancing the therapeutic efficacy of this vaccine by fusion to various cytokine genes, including interleukin-2 (IL-2), interleukin-4 (IL-4), or granulocyte-macrophage colony-stimulating factor. In a therapeutic model, N'-neu-IL-2 DNA vaccine was significantly better than N'-neu DNA vaccine, and N'-neu DNA vaccine was significantly better than control DNA or N'-neu-IL-4 DNA vaccine. The therapeutic efficacy of DNA vaccines was correlated with tumor infiltration of CD8+ T cells. Depletion of CD8+ T cells completely abolished the therapeutic effects of N'-neu-IL-2 DNA vaccine and N'-neu DNA vaccine. Depletion of CD4+ T cells after tumor implantation had no influence on N'-neu-IL-2 DNA vaccine, but enhanced the therapeutic efficacy of N'-neu DNA vaccine. Our results demonstrate that rat N'-neu DNA vaccine has a therapeutic effect on established tumor through the CD8+ T-cell-dependent pathway. Depletion of CD4+ T cells or fusion to the IL-2 gene can thus further enhance the therapeutic effects of N'-neu DNA immunization on mouse tumor expressing endogenous p185neu.
 ...
PMID:Therapeutic HER2/Neu DNA vaccine inhibits mouse tumor naturally overexpressing endogenous neu. 1529 76

SRL172, non-specific immunological adjuvant downregulates interleukin-4, upregulates interleukin-2 production, switching towards a T-helper-1 response, induces an increase in natural killer cells and activates antigen presenting cells. The human epidermal growth factor receptor 2 gene amplification is frequently observed in a number of primary tumors, suggesting that the overexpression of this growth factor receptor may contribute to transformation and tumorigenesis. Gene amplification occurs in approximately 15-20% of human breast cancers Amplification is associated with aggressive tumor behavior and shortened survival. Trastuzumab, humanized anti-HER-2 antibody targets the HER-2 protein with high affinity. Trastuzumab when used alone or in combination with cytotoxic chemotherapy can induce reasonably durable remissions in a significant percentage of women with metastatic breast cancer whose tumors demonstrate Her-2/neu gene amplification. One of the proposed mechanisms of trastuzumab antitumor action is through antibody dependent cellular cytotoxocity. Pivotal study showed that Trastuzumab+IL-2 resulted in NK cell expansion with enhanced in vitro targeted killing of HER-2-expressing cells. SRL172 by increasing IL-2 production and number of natural killer cells may augment the efficacy of trastuzumab in metastatic breast cancer patients. SRL 172 increases IL-2 production and the number of NK cells in vivo. Based on these data, a clinical trial can be performed to test whether SRL 172 added to trastuzumab is safe and more efficacious.
 ...
PMID:SRL172 (killed Mycobacterium vaccae) may augment the efficacy of trastuzumab in metastatic breast cancer patients. 1560 48

DNA vaccine represents a novel method to elicit immunity against infectious disease. Lipopolysaccharide (LPS) copurified with plasmid DNA may affect therapeutic efficacy and immunological response. We aimed to study the effect of LPS on the therapeutic efficacy of HER-2/neu DNA vaccine in a mouse tumor animal model. Plasmid DNA purified from commercial EndoFree plasmid purification kits functioned as a better therapeutic DNA vaccine than that purified from Non-EndoFree purification kit, which contains >or=0.5 microg LPS per 100 mg DNA plasmid. To further investigate the effect of LPS on the therapeutic efficacy of DNA vaccine, increasing amount of LPS was added to endotoxin-free plasmid DNA, and inoculated on mice with established tumors. One mug of LPS significantly attenuated the therapeutic effect of neu DNA vaccine and increased Th2 immune responses bias with interleukin-4 cytokine production. In contrast, high amount (100 microg) of LPS enhanced the therapeutic efficacy of neu DNA vaccine with an increase of cytotoxic T lymphocyte response and Th1 immune response. The effect of LPS on DNA vaccine was diminished when the tumor was grown in toll-like receptor 4 (TLR4)-mutant C3H/HeJ mice. Our results indicate that variation in the LPS doses exerts opposing effects on the therapeutic efficacy of DNA vaccine, and the observed effect is TLR4 dependent.
 ...
PMID:The opposing effects of lipopolysaccharide on the antitumor therapeutic efficacy of DNA vaccine. 1805 24