Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. LPS phase I trial revealed MTD I of 1.0 ng/kg body weight and MTD II of 5.0 ng/kg body weight, the latter given together with ibuprofen (1,600 mg). 2. LPS phase II trial, using 4,0 ng/kg body weight plus ibuprofen in a biweekly schedule didn't show any response in patients with non-small cell lung cancer but 1 CR and 2 PR (13% response rate) in colorectal cancer patients. 3. The LPS tolerance is specific for each cytokine and mediator in regard to the kinetic and degree of its development. INF-gamma prevents the tolerance development to several cytokines with the exception of IL-8. 4. No tolerance was found in cell adhesion, phospholipase A2, and soluble TNF receptor I and II. Priming of ex vivo cytokine production of cytokines was found in mononuclear cells. 5. Synthetic LPS partial structure SDZ-MRL 953 (I) induces a cytokine pattern, which is profoundedly different from that of LPS, (II) with an inverse TNF to G-CSF relation, (III) is (without any ibuprofen treatment) remarkably low toxic, (IV) and downregulates the TNF-response to LPS markedly.
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PMID:Endotoxin (Salmonella abortus equi) in cancer patients. Clinical and immunological findings. 852 30

Granulocyte-macrophage colony-stimulating factor (GM-CSF), in addition to being a haematopoietic growth factor, has been shown to stimulate in vitro the production of interleukins 1, 6 and 8 (IL-1, IL-6 and IL-8), tumour necrosis factor-alpha (TNF-alpha) and GM-CSF by polymorphonuclear cells (PMNs), alveolar macrophages (AMs), fibroblasts and endothelial cells of the lung, and the growth and differentiation of resident alveolar macrophages. The aim of this study was to establish whether recombinant GM-CSF (rhGM-CSF), administered subcutaneously at a dose of 5 micrograms.kg-1 for 3 days in five patients with unresectable non-small cell lung cancer before starting chemotherapy, induces an increase in the alveolar cell count, and whether these cellular lung variations may be related to increases in the above-mentioned cytokines. In the bronchoalveolar lavage fluid (BALF) total cell count, polymorphonuclear cells, neutrophils, and alveolar macrophages increased significantly in comparison with the baseline, and the extent of variation of the BAL cell count was considerably greater than that of the circulating leucocytes. The mean levels of all the cytokines increased, but a significant difference with respect to the basal condition was observed only for IL-6 and IL-8. After rhGM-CSF treatment, significant correlations were found between neutrophil counts and the levels of IL-6 and IL-8. In conclusion, rhGM-CSF administration induces a cellular expansion in the lung, and the neutrophil increase appears to be related to increased levels of IL-8.
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PMID:Blood cell redistribution in the lung after administration of recombinant human granulocyte-macrophage colony-stimulating factor. 857 86

Interleukin-8 (IL-8) is an 8 kD chemokine and angiogenic factor produced by alveolar macrophages, endothelial cells, monocytes, fibroblasts, T lymphocytes, and epithelial cells in response to a variety of stimuli, including LPS, TNF-alpha, IL-1, IL-7, and hypoxia. Pulmonary tumors produce a variety of growth factors and cytokines that may act in both autocrine and paracrine fashion. A549, a well-characterized human lung adenocarcinoma line, was cloned for different levels of IL-8 production by limiting dilution. Clone 3B4 produced 361 +/- 73 pg/ml, and clone 2B2 produced 7818 +/- 614 pg/ml of IL-8 (p = 0.003). Clone 3B4 proliferated at 1.7 times the rate of 2B2. Anti-IL-8 reversed the decrement in proliferation of clone 2B2 by 50%, but recombinant IL-8 decreased the proliferation of 3B4 by 40-55% compared with control. In addition to A549, three other non-small cell lung cancer (NSCLC) lines showed significantly decreased proliferation in response to exogenous recombinant IL-8 (5-30 ng/ml; p < 0.05). These findings suggest that in addition to its chemotactic and angiogenic activities, IL-8 may inhibit lung tumor proliferation by both autocrine and paracrine pathways.
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PMID:Interleukin-8 inhibits non-small cell lung cancer proliferation: a possible role for regulation of tumor growth by autocrine and paracrine pathways. 864 Apr 52

The salient feature of solid tumor growth is the strict dependence on local angiogenesis. We have previously demonstrated that IL-8 is an angiogenic factor present in freshly isolated specimens of human non-small cell lung cancer (NSCLC). Using a model of human NSCLC tumorigenesis in SCID mice, we now report that IL-8 acts as a promoter of human NSCLC tumor growth through its angiogenic properties. Passive immunization with neutralizing antibodies to IL-8 resulted in more than 40% reduction in tumor size and was associated with a decline in tumor-associated vascular density and angiogenic activity. IL-8 did not act as an autocrine growth factor for NSCLC proliferation. The reduction in primary tumor size in response to neutralizing antibodies to IL-8 was also accompanied by a trend toward a decrease in spontaneous metastasis to the lung. These data support the notion that IL-8 plays a significant role in mediating angiogenic activity during tumorigenesis of human NSCLC, thereby offering a potential target for immunotherapy against solid tumors.
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PMID:Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice. 867 90

We examined the importance of IL-8 receptor B mRNA expression in the growth of non-small cell lung cancer (NSCLC). Using antisense oligonucleotide ICN 197, we were able to inhibit IL-8 R B mRNA expression in vitro. The sequence specific effect of antisense oligonucleotide and down-regulation of IL-8 R B mRNA was shown by Reverse Transcription Polymerase Chain Reaction (RT-PCR) and Southern blot analysis. The proliferation of treated cells was measured by 3H thymidine incorporation. We found that treatment of NSCLC cells caused reversible growth inhibition and reversible down regulation of IL-8 R B mRNA. Furthermore, we observed that the treatment of nude mice with oligonucleotide ICN 197 inhibited the growth of tumors developed from NSCLC cells injected subcutaneously. Our data in vitro suggest that IL-8 receptor B mRNA expression is required to maintain the proliferative rate of NSCLC. Based on the data in vivo. oligonucleotide ICN 197 may be considered for the development of novel therapeutic treatment for lung cancer.
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PMID:Reversible inhibition of IL-8 receptor B mRNA expression and proliferation in non-small cell lung cancer by antisense oligonucleotides. 904 16

The interactions between tumor cells and surrounding stromal elements may promote the release of angiogenic factors. Although interleukin 8 (IL-8) is a major angiogenic factor in non-small cell lung cancer (NSCLC), the stromal contribution to IL-8 expression in primary NSCLC remains to be defined. To elucidate the role of stromal elements in NSCLC IL-8 production, normal pulmonary fibroblasts were cocultured with six representative NSCLC lines in direct and transwell assays. IL-8 transcripts and protein were consistently induced in fibroblasts and a subset of NSCLCs as a consequence of tumor/stromal coculture. In these cocultures, IL-8 was induced by IL-1alpha and an additional, as yet unidentified, soluble factor. These data underscore the importance of tumor/stromal interaction in the production of angiogenic peptides such as IL-8 in NSCLC.
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PMID:The angiogenic factor interleukin 8 is induced in non-small cell lung cancer/pulmonary fibroblast cocultures. 1066 74

Because routine histopathological examination of primary non-small cell lung cancer does not predict disease outcome, we correlated disease outcome with the expression level of multiple genes that regulate distinct steps of the metastatic process in 60 formalin-fixed, paraffin-embedded, archival specimens of stage I lung carcinoma from patients undergoing curative surgery at the M. D. Anderson Cancer Center. The expression of E-cadherin (related to cell cohesion), type IV collagenase [matrix metalloproteinase (MMP)-2 and MMP-9, related to invasion], and three angiogenic molecules, basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor, and interleukin 8, were examined by a colorimetric in situ mRNA hybridization technique. The expression levels of the individual genes analyzed by a Cox univariate analysis were not prognostic. In contrast, the ratio between expression of type IV collagenases (mean of the expression of MMP-2 and MMP-9) and E-cadherin, the MMP:E-cadherin ratio (measured at the periphery of each tumor), was significantly higher in patients with recurrent disease than in patients who remained disease free (P = 0.00003). Longer overall survival and reduced disease recurrence rates were significantly associated with a lower MMP:E-cadherin ratio (<2) by a Kaplan-Meier survival analysis (P = 0.0002 and P = 0.0001, respectively). Multiple covariate analyses of overall and disease-free survival also concluded that the MMP:E-cadherin ratio was a significant prognostic factor when corrected for age (P = 0.0001). Determination of this gene expression ratio in individual human lung cancers might therefore be used to direct tailored treatment for individual patients with resectable lung cancer.
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PMID:Differential expression of E-cadherin and type IV collagenase genes predicts outcome in patients with stage I non-small cell lung carcinoma. 1074 98

Cyclooxygenase-2 (COX-2), the enzyme that converts arachidonic acid to prostaglandins, is overexpressed in a variety of different tumors, including those of the colon, pancreas, lung, and head and neck. We used in situ hybridization with a digoxgenin-labeled COX-2 antisense riboprobe to assess the presence of strong or intermediate versus weak or absent COX-2 expression in specimens from 160 patients with stage I non-small cell lung cancer (NSCLC). Of these, 3 specimens had strong expression, 69 had intermediate expression of COX-2, 24 had weak expression, and 64 had no detectable COX-2. The strength of COX-2 expression was associated with a worse overall survival rate (P = 0.001) and a worse disease-free survival rate (P = 0.022). The median survival times for the strong, intermediate or weak, and null COX-2 expressors were 1.04, 5.50, and 8.54 years, respectively. Interestingly, all three specimens with strong COX-2 expression came from patients who died within 18 months. Retinoic acid receptor beta (RAR-beta) is a nuclear retinoid receptor whose expression is frequently lost in aerodigestive tract carcinogenesis. We previously demonstrated that expression of RAR-beta in stage I NSCLC indicates a poor prognosis. Retinoids have been shown to prevent induction of COX-2 by mitogens and tumor promoters. Expression of COX-2 correlated with RAR-beta expression (P = 0.053), but not with k-ras mutational status, vascular endothelial growth factor, basic fibroblast growth factor, interleukin 8 levels, or other markers of angiogenesis, invasion, and metastases. Thus, like RAR-beta positivity, COX-2 overexpression appears to portend a shorter survival among patients with early stage non-small cell lung cancer. Future studies of RAR-beta and COX-2 regulation in NSCLC should further the development of prevention and therapy interventions with retinoids and/or COX-2 antagonists in this patient population.
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PMID:Cyclooxygenase-2 overexpression is a marker of poor prognosis in stage I non-small cell lung cancer. 1130 34

Interleukin-8 (IL-8) is a pleiotropic cytokine that has also been shown to exert effects relevant to cancer growth and progression. Cancer progression is believed to be contributed to by the ability of this cytokine to promote angiogenesis and mitogenic effects. As IL-8 production at the tumor site may determine elevated serum levels of this cytokine because of hematogenous leakage, it is conceivable that patients with high IL-8 serum levels may have tumors actively producing this cytokine. The aim of this study was, therefore, to assess IL-8 serum levels in 60 non-small cell lung cancer (NSCLC) patients undergoing chemotherapy and to correlate them with prognosis. IL-8 serum levels were found to be significantly elevated in cancer patients with respect to controls. Moreover, IL-8 serum levels were shown to be significantly increased in stage IV patients compared with stage III patients. When basal IL-8 serum levels in cancer patients were analyzed according to response to chemotherapy, responders were shown to have significantly lower IL-8 serum levels than nonresponders. On univariate analysis, the IL-8 serum level was included among the variables capable of affecting both overall survival (OS) and time to treatment failure (TTF). However, multivariate analysis failed to demonstrate an independent prognostic significance for IL-8 serum levels. In conclusion, this study showed that IL-8 serum levels were elevated in advanced NSCLC patients and correlated with both OS and TTF, but they were shown not to be an independent prognostic factor.
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PMID:Elevated serum levels of interleukin-8 in advanced non-small cell lung cancer patients: relationship with prognosis. 1251 12

Histone deacetylase (HDAC) inhibitors are emerging as a new class of anticancer agents for the treatment of solid and hematological malignancies. Although HDAC inhibitors induce cell death through an apoptotic process, little is known about the molecular events that control their effectiveness. In this study, we demonstrate that HDAC inhibitors are limited in their ability to induce apoptosis in non-small cell lung cancer (NSCLC) cell lines despite their ability to effectively inhibit deacetylase activity. Because the anti-apoptotic transcription factor NF-kappa B has been shown to be under the control of HDAC-mediated repression, we analyzed whether HDAC inhibitors activated NF-kappa B in NSCLC cells. HDAC inhibitors effectively stimulated endogenous NF-kappa B-dependent gene expression by up-regulating IL-8, Bcl-XL, and MMP-9 transcripts. The ability of HDAC inhibitors to increase NF-kappa B transcriptional activity was not associated with signaling events that stimulated nuclear translocation, but rather modulated the transactivation potential of the RelA/p65 subunit of NF-kappa B. The inhibition of HDAC activity was associated with the recruitment of the p300 transcriptional co-activator to chromatin in an Akt-dependent manner. Moreover, Akt directly phosphorylated p300 in vitro and was required for stimulating the transactivation potential of the co-activator following the addition of HDAC inhibitors. Selective inhibition of either the phosphoinositide 3-kinase/Akt pathway, or NF-kappa B itself blocked the ability of HDAC inhibitors to activate NF-kappa B and dramatically sensitized NSCLC cells to apoptosis following of the addition of HDAC inhibitors. Our study indicates that the ineffectiveness of HDAC inhibitors to induce apoptosis in NSCLC cancer cells is associated with the ability of these molecules to stimulate NF-kappa B-dependent transcription and cell survival.
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PMID:Ineffectiveness of histone deacetylase inhibitors to induce apoptosis involves the transcriptional activation of NF-kappa B through the Akt pathway. 1264 66


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