Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sialyl-Lewis x epitopes and MUC5AC protein are known to be overexpressed in mucins secreted by patients suffering from various respiratory diseases. To investigate the mechanisms by which airway inflammatory agents mediate the expression of sialyl-Lewis x epitopes and MUC5AC mucin, we examined the effects of tumor necrosis factor (TNF)-alpha and epidermal growth factor (EGF) in the human lung carcinoma cell line, NCI-H292. Basal expression levels of hST3GalIV, FUT3 and C2/4GnT mRNA, involved in the biosynthesis of sialyl-Lewis x, were higher than those of other glycosyltransferases in NCI-H292 cells. TNF-alpha induced expression of hST3GalIV, FUT3, C2/4GnT and MUC5AC mRNAs in NCI-H292 cells. When cells were pretreated with U73122, a phosphatidylinositol-phospholipase C (PI-PLC) inhibitor, the expression of these glycosyltransferase mRNAs was suppressed. Treating cells with EGF induced the down-regulation of these glycosyltransferase mRNAs and sialyl-Lewis x epitopes, while inducing an increase in expression of MUC5AC mRNA. These EGF-mediated effects on the glycosyltransferase and MUC5AC mRNAs were blocked when cells were first exposed to AG1478, an EGF receptor tyrosine kinase inhibitor. These findings suggest that the expression of sialyl-Lewis x epitopes, which is regulated separately from the expression of MUC5AC protein, may be controlled through pathways such as the EGF receptor tyrosine kinase and PI-PLC signaling cascades in NCI-H292 cells.
 ...
PMID:Regulation of sialyl-Lewis x epitope expression by TNF-alpha and EGF in an airway carcinoma cell line. 1586 35

Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is an active agent in non-small cell lung cancer, and rapidly relieves bronchorrhea in patients with bronchioloalveolar carcinoma before the improvement of radiological findings. In addition, epidermal growth factor regulates mucin secretion in normal airway goblet cells. The present study was designed to clarify whether gefitinib modifies mucin production in lung cancer cell lines apart from its anti-proliferative effects, using A549 adenocarcinoma and NCI-H292 mucoepidermoid carcinoma cells expressing EGFR and MUC5AC mRNA. Mucin synthesis was measured by RT-PCR and ELISA, and MAPK and Akt, the downstream targets of EGFR, were examined by Western blotting assay. The clinically-achievable concentration of 1muM gefitinib inhibited the growth of both cells by only 10%, but gefitinib suppressed MUC5AC mRNA levels subsequent to a decrease in intracellular and secreted MUC5AC protein. Gefitinib also inhibited the phosphorylation of MAPK and Akt, and the selective inhibitors PD98059 and LY294002 also suppressed MUC5AC protein synthesis. These findings suggest that gefitinib may inhibits MUC5AC synthesis, at least in part, through MAPK and Akt signaling pathways. Thus, gefitinib inhibits mucin production, which is encouraging for trials involving its use against bronchorrhea in patients with lung cancer.
Lung Cancer 2005 Oct
PMID:Gefitinib inhibits MUC5AC synthesis in mucin-secreting non-small cell lung cancer cells. 1600 52

Over the past 30 years, a relatively simple growth factor and its cognate receptor have provided seminal insights into the understanding of the genetic basis of cancer, as well as growth factor signalling. The epidermal growth factor (EGF), its cognate receptor (EGFR) and related family members have been shown to be important in normal, as well as the malignant growth of many cell types including: glioblastomata, astrocytomas, medulloblastomata, non-small cell lung carcinoma (NSCLC) and breast cancer. This review summarises the history of the EGFR gene and the v-ErbB oncogene, as well as diverse approaches developed to inhibit EGFR activity. The two most advanced therapies use either small-molecule cell membrane permeable kinase inhibitors or antibodies which prevent receptor activation. Recent clinical trials indicate that certain NSCLC patients have mutations in the EGFR gene which makes them more responsive to kinase inhibitors. These mutations appear to enhance the ability of the ligand to activate EGFR activity and also prolong the binding of the EGFR inhibitor to the kinase domain. Evidence to date suggests that these EGFR mutations in NSCLC occur more frequently in Japan than in the western hemisphere. Although these mutations are correlated with enhanced efficacy to the inhibitors in NSCLC, they can not explain or predict the sensitivity of many other cancer patients to the beneficial effects of the EGFR kinase inhibitors or antibody mediated therapy. As with as other small-molecule kinase inhibitors and susceptible diseases (e.g., imatinib and chronic myeloid leukaemia), resistance to EGFR inhibitors has been reported recently, documenting the requirement for development of multi-pronged therapeutic approaches. EGFR kinase inhibitors are also being evaluated as adjuvants in hormonal therapy of breast cancer - especially those which overexpress EGFR. Genetically engineered antibodies specific for the EGFR family member ErbB2 have been developed which show efficacy in the treatment of primary, and prevent the relapse of, breast cancer. Clearly, the EGF/EGFR signalling cascade has, and continues to play, an important role in the development of novel anticancer targeted therapies.
 ...
PMID:The epidermal growth factor receptor gene family as a target for therapeutic intervention in numerous cancers: what's genetics got to do with it? 1618 55

The exact role of a disintegrin and metalloproteinase with thrombospondin motifs-1 (ADAMTS-1) and the underlying mechanism of its involvement in tumor metastasis have not been established. We have now demonstrated that overexpression of ADAMTS-1 promotes pulmonary metastasis of TA3 mammary carcinoma and Lewis lung carcinoma cells and that a proteinase-dead mutant of ADAMTS-1 (ADAMTS-1E/Q) inhibits their metastasis, indicating that the prometastatic activity of ADAMTS-1 requires its metalloproteinase activity. Overexpression of ADAMTS-1 in these cells promoted tumor angiogenesis and invasion, shedding of the transmembrane precursors of heparin-binding epidermal growth factor (EGF) and amphiregulin (AR), and activation of the EGF receptor and ErbB-2, while overexpression of ADAMTS-1E/Q inhibited these events. Furthermore, we found that ADAMTS-1 undergoes auto-proteolytic cleavage to generate the NH(2)- and COOH-terminal cleavage fragments containing at least one thrombospondin-type-I-like motif and that overexpression of the NH(2)-terminal ADAMTS-1 fragment and the COOH-terminal ADAMTS-1 fragment can inhibit pulmonary tumor metastasis. These fragments also inhibited Erk1/2 kinase activation induced by soluble heparin-binding EGF and AR. Taken together, our results suggest that the proteolytic status of ADAMTS-1 determines its effect on tumor metastasis, and that the ADAMTS-1E/Q and the ADAMTS-1 fragments likely inhibit tumor metastasis by negatively regulating the availability and activity of soluble heparin-binding EGF and AR.
 ...
PMID:Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively. 1631 35

Autocrine growth factor stimulation resulting in growth self-sufficiency is a hallmark of cancer. Classically, non-small-cell lung cancer (NSCLC) cells have autocrine epidermal growth factor stimulation through coexpression of receptors and ligands. In addition to epidermal growth factor receptor and other growth factor ligand-receptor autocrine loops, increasing evidence suggests important roles for cytokines in mediating intracellular signaling events important in cell growth and survival. Interleukin-6 (IL-6) has been shown to activate pathways important in tumorigenesis including Janus kinase/signal transducer and activator of transcription, phosphotidylinositol 3-kinase/Akt, and extracellular signal-regulated kinase signaling. Using immunohistochemistry, we demonstrate that NSCLC specimens have tumor expression of IL-6 and IL-6 receptor components gp80 and gp130. These results suggest that IL-6 autocrine signaling might contribute to downstream signaling events in NSCLC and further support the concept of multiple autocrine pathways contributing to the pathogenesis of NSCLC.
Clin Lung Cancer 2006 Jan
PMID:Autocrine interleukin-6/interleukin-6 receptor stimulation in non-small-cell lung cancer. 1651 82

The use of alpha(1,3)galactosyltransferase (alphaGT) as a method of inducing hyperacute rejection of tumors has been gaining interest recently. However, the approach is based in part on the sensitivity of each tumor line to the effects of complement lysis. Tumors expressing complement resistance factors such as membrane cofactor (CD46), decay accelerating factor (CD55) and protectin (CD59) have been shown to be more resistant to complement mediated lysis. Anchored to the membrane by a glycosylphosphoinositol moiety (GPI-anchored), CD55 and CD59 can be cleaved by Bacillus thuringiensis phosphatidylinositol-specific phospholipase C (PIPLC). Complement resistant A549 human lung carcinoma cells were engineered to express both the murine alphaGT gene and the B. thuringiensis PIPLC gene to alleviate complement resistance and enhance alphagal-mediated cancer killing. The PIPLC native signal sequence was replaced with the human epidermal growth factor signal sequence, EGFssPIPLC, to induce secretion from A549. Expression of EGFssPIPLC resulted in complete removal of CD55 and CD59 while sparing the non-GPI-anchored CD46. Results demonstrated that A549 cells transduced with two recombinant retroviral vectors carrying the alphaGT and EGFssPIPLC genes expressed high levels of alphagal epitope and exhibited a 5-fold increase in sensitivity to anti-alphagal mediated complement lysis.
 ...
PMID:Co-expression of alpha(1,3)galactosyltransferase and Bacillus thuringiensis PIPLC enhances hyperacute rejection of tumor cells. 1661 94

Mevalonate metabolites play an essential role in transducing epidermal growth factor (EGF) receptor (EGFR)-mediated signaling, as several of these metabolites are required for the function of this receptor and the components of its signaling cascades. Thus, the depletion of mevalonate metabolites may have a significant effect on EGFR function. Lovastatin is a specific and potent inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of the mevalonate pathway. Targeting 3-hydroxy-3-methylglutaryl CoA reductase using lovastatin induces a potent tumor-specific apoptotic response in a variety of tumor types at therapeutically achievable levels of this drug. The effects of lovastatin on EGFR function and the potential combination effects with EGFR tyrosine kinase inhibitors, such as gefitinib, were evaluated. Lovastatin treatment inhibited EGF-induced EGFR autophosphorylation and its downstream signaling cascades by 24 hours. Combining lovastatin and gefitinib showed enhanced inhibition and cooperative cytotoxicity in a variety of cell lines that included all eight squamous cell carcinomas, four non-small cell lung carcinoma, and four colon carcinoma cell lines tested. Isobologram analyses confirmed that this combination was synergistic, inducing a potent apoptotic response. A phase I study has shown the safety and potential clinical benefit of high-dose lovastatin in patients with recurrent squamous cell carcinoma. The use of lovastatin, which is metabolized by CYP3A4, is contraindicated with drugs, such as gefitinib and erlotinib, which are also metabolized by CYP3A4 due to greatly enhanced toxicity. Rosuvastatin, a relatively novel potent mevalonate pathway inhibitor that is not metabolized significantly by CYP3A4, is a more appropriate statin to combine with either erlotinib or gefitinib. The combination of erlotinib and rosuvastatin has been proposed for a phase I/II study in advanced non-small cell lung carcinoma.
 ...
PMID:Strategies to enhance epidermal growth factor inhibition: targeting the mevalonate pathway. 1685 22

Gefitinib (Iressa), an epidermal growth factor inhibitor approved for treatment of advanced nonsmall cell lung carcinoma, is associated with an acneiform distributed folliculitis. Treatment attempts for this folliculitis have been noted in the literature, but photodocumentation of results has not been reported. We report 3 consecutive cases of gefitinib-associated folliculitis with photodocumentation of their treatment responses to combination therapy with topical metronidazole and oral tetracyclines.
 ...
PMID:Treatment of gefitinib-associated folliculitis. 1701 Jul 57

There is significant evidence that both angiotensin I converting enzyme inhibitors (ACEI) and type 1 and type 2 angiotensin 2 (A2) receptor blockers may inhibit tumor growth. The finding is supported by many reports where these two classes of drugs showed cytostatic effects on the cultures of several lines of both normal and neoplastic cells. These drugs often transformed the cellular biochemical structures, especially in neoplastic cell lines. The same drugs also delayed the growth of different types of tumors in a variety of experimental animals (breast and lung carcinoma in mice; sarcomas, squamous cell carcinomas and hepatocellular carcinomas in rats), and there are a few reports of successful treatment of a limited number of cases of Kaposi sarcoma and gliomas with these drugs. Retrospective studies in hypertensive subjects treated with ACEI or A2 receptor blockers also seem to indicate that the incidence and growth of different neoplasms was delayed when these patients were compared to hypertensive patients receiving alternate medications. There is strong indication that the pharmacologic effect of these drugs may be exerted by reduction or inhibition of the synthesis of angiotensin 2. A2 is a powerful mitogen and its effect on cellular growth is exerted through stimulation of many factors, including transforming growth factor beta (TGFbeta), epidermal growth factor (EGF), smooth muscle actin (SMA), and tyrosine kinase. A2 also regulates apoptotic mechanisms and angiogenesis. The pharmacologic action of most of these drugs, however, is not necessarily limited to downregulaton of A2. Many ACEI, especially those containing the sulfhydryl (SH group), possess antioxidant or metalloprotease inhibitory properties per se. These experimental and retrospective data justify clinical testing of these drugs in appropriate randomized trials. Several such trials are currently in process. If these trials confirm the experimental and retrospective studies, these agents will provide a significant contribution to the therapeutic treatment of many malignancies in humans.
 ...
PMID:Potential deployment of angiotensin I converting enzyme inhibitors and of angiotensin II type 1 and type 2 receptor blockers in cancer chemotherapy. 1701 54

Angiotensin II (AII) is a multifunctional bioactive peptide, and host renin-angiotensin system (RAS) is closely associated with tumor growth. Recent reports have described that AII is a proangiogenic growth factor, and that Angiotensin II type 1 (AT1) receptor antagonists reduce tumor growth and tumor-associated angiogenesis. In this paper, we investigated the participation of AT1 receptor-signaling in cancer progression using murine Lewis lung carcinoma (LLC) cells, which express AT1 receptor, and AT1a receptor gene-deficient (AT1a-/-) mice. When LLC cells were implanted subcutaneously into wild-type (WT) mice, developed tumors showed intensive angiogenesis with an induction of vascular endothelial growth factor (VEGF) a. Compared with WT mice, tumor growth and tumor-associated angiogenesis was reduced in AT1a-/- mice with reduced expression of VEGFa. In AT1a-/- mice, administration of the AT1 receptor antagonist, TCV-116, showed further reductions of tumor growth, tumor-associated angiogenesis, and VEGFa expression. In vitro study, the expression of VEGFa mRNA and the production of VEGFa protein in LLC cells were significantly increased by AII, which were cancelled by AT1 receptor antagonist, CV-11974. Although the expression of other angiogenic factors, such as angiopoietin-1, angiopoietin-2, epidermal growth factor, and VEGF receptor 2 mRNA, was also investigated in tumor tissues, the expression of VEGFa was most correlated with tumor size among those other angiogenic factors. VEGFa induction by AT1 receptor-signaling in both host and tumor tissues is one of key regulators of tumor growth and tumor-associated angiogenesis. In conclusion, tumor tissue RAS as well as host tissue RAS were found to have an important role in tumor growth. AT1 receptor-signaling blockade may be a novel and effective target in the treatment of cancer.
 ...
PMID:Roles for host and tumor angiotensin II type 1 receptor in tumor growth and tumor-associated angiogenesis. 1731 97


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