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

It has been widely demonstrated that neo-angiogenesis and its mediators (i.e. vascular endothelial growth factor), represent useful indicators of poor prognosis in non small cell lung carcinoma. In order to verify whether neovascularization and vascular endothelial growth factor may be considered useful markers of clinical outcome also in the small cell lung cancer subgroup, we retrospectively investigated a series of 75 patients with small cell lung carcinoma treated by surgery between 1980 and 1990. Immunohistochemically-detected microvessels and vascular endothelial growth factor expressing cells were significantly associated with poor prognosis, as well as with nodal status and pathological stage. In fact, patients whose tumours had vascular count and vascular endothelial growth factor expression higher than median value of the entire series (59 vessels per 0.74 mm(2) and 50% of positive cells, respectively), showed a shorter overall and disease-free survival (P=0.001, P=0.001; P=0.008, P=0.03). Moreover, the presence of hilar and/or mediastinal nodal metastasis and advanced stage significantly affected overall and disease-free interval (P=0.00009, P=0.00001; P=0.0001, P=0.00001). At multivariate analysis, only vascular endothelial growth factor expression retained its influence on overall survival (P=0.001), suggesting that angiogenic phenomenon may have an important role in the clinical behaviour of this lung cancer subgroup.
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PMID:A high vascular count and overexpression of vascular endothelial growth factor are associated with unfavourable prognosis in operated small cell lung carcinoma. 1187 May 37

We have previously shown that 4-anilinoquinazolines can be potent inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt-1 and KDR) tyrosine kinase activity. A novel subseries of 4-anilinoquinazolines that possess basic side chains at the C-7 position of the quinazoline nucleus have been synthesized. This subseries contains potent, nanomolar inhibitors of KDR (median IC(50) 0.02 microM, range 0.001-0.04 microM), which are comparatively less potent vs Flt-1 tyrosine kinase (median IC(50) 0.55 microM, range 0.02-1.6 microM). The compounds also retain some inhibitory activity against the tyrosine kinase associated to the endothelial growth factor receptor (EGFR) (median IC(50) 0.2 microM, range 0.075-0.8 microM) but demonstrate selectivity vs that associated to the FGF receptor 1 (median IC(50) 2.5 microM, range 0.9-19 microM). This selectivity profile is also evident in a growth factor-stimulated human endothelial cell (HUVEC) proliferation assay (i.e., inhibition of VEGF > EGF > FGF), with inhibition of VEGF-induced proliferation being achieved at nanomolar concentrations (median IC(50) 0.06 microM). Further examination of compound 2 (ZD6474) in recombinant enzyme assays revealed excellent selectivity for the inhibition of KDR tyrosine kinase (IC(50) 0.04 microM) vs the kinase activity of erbB2, MEK, CDK-2, Tie-2, IGFR-1R, PDK, PDGFRbeta, and AKT (IC(50) range: 1.1 to >100 microM). Anilinoquinazolines possessing basic C-7 side chains exhibited markedly improved aqueous solubility over previously described anilinoquinazolines possessing neutral C-7 side chains (up to 500-fold improvement at pH 7.4). In addition, aqueous solubility of the neutral fraction present at pH 7.4 of the basic subseries of anilinoquinazoline proved to be higher than that of the neutral analogue 1 (ZD4190). Oral administration of representative compounds to mice (50 mg/kg) produced plasma levels between 0.2 and 3 microM at 24 h after dosing. Our development candidate 2 demonstrated a very attractive in vitro profile combined with excellent solubility (330 microM at pH 7.4) and good oral bioavailability in rat and dog (> 80 and > 50%, respectively). This compound demonstrated highly significant, dose-dependent, antitumor activity in athymic mice. Once daily oral administration of 100 mg/kg of compound 2 for 21 days inhibited the growth of established Calu-6 lung carcinoma xenografts by 79% (P < 0.001, Mann Whitney rank sum test), and substantial inhibition (36%, P < 0.02) was evident with 12.5 mg/kg/day.
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PMID:Novel 4-anilinoquinazolines with C-7 basic side chains: design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitors. 1188 99

Three cases of alpha-fetoprotein (AFP)-producing lung carcinoma were studied histologically and immunohistochemically. Samples were obtained from two men and one woman who ranged in age from 64 to 71 years. Serum AFP levels for the three samples were 9826, 74.4 and 24.3 ng/mL. One case was classified as stage IIIA and two as stage IIIB. Two cases were diagnosed as large cell neuroendocrine carcinoma, and AFP expression was detected immunohistochemically. One of these samples showed differentiation to a hepatoid carcinoma, while the other was combined with a squamous cell carcinoma. The remaining case was a squamous cell carcinoma, and AFP was detected in only some of the tumor cells. All patients died within 2 years. The Ki-67 labeling indices of the AFP-producing pulmonary carcinomas (30.2 +/- 4.6%) were significantly higher than those of AFP-negative pulmonary carcinomas (P < 0.05). The high proliferative activity, advanced stage at presentation, vascular endothelial growth factor expression and vascular invasion observed in these tumors may explain the poor prognosis of AFP-producing lung carcinomas.
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PMID:Alpha-fetoprotein-producing lung carcinoma: report of three cases. 1194 Feb 6

We have analysed the predictive and prognostic information in preoperatively collected serum levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in patients clinically evaluated as operable non-small cell lung cancer (NSCLC). Fifty-eight patients with operable NSCLC were included. VEGF and bFGF levels in serum were analysed using enzyme linked immunosorbent assays (Quantikine human VEGF and Quantikine HS human FGF basic, R&D Systems). Univariate analysis demonstrated that tumour volume, platelet counts, VEGF and bFGF were significant prognostic factors. However, only bFGF remained significant in the multivariate analysis (P=0.014). Significant correlation's were demonstrated between VEGF levels and tumour volume (r=0.33; P=0.012) and platelet count (r=0.43; P=0.001). bFGF levels correlated significant with recurrent disease (r=0.34; P=0.01), platelet count (r=0.53, P<0.001) and performance status (r=0.29; P=0.029). Furthermore, bFGF levels and VEGF levels correlated significantly (r=0.44; P<0.001). We conclude that elevated circulating angiogenic cytokines correlate with tumour volume, higher relapse risk and poorer survival in patients with operable non-small cell lung cancer.
Lung Cancer 2002 Jul
PMID:Elevated preoperative serum levels of angiogenic cytokines correlate to larger primary tumours and poorer survival in non-small cell lung cancer patients. 1205 68

Inflammatory conditions are associated with tumor development. IL-1beta is a multifunctional and proinflammatory cytokine that affects nearly all types of cells. To investigate the role of IL-1beta in tumor growth in vivo, we transduced the retroviral vector coding human IL-1beta gene into mouse Lewis lung carcinoma (LLC) cells and subsequently inoculated the transformant (LLC/IL-1beta) to syngeneic C57BL/6 mice. Tumors derived from LLC/IL-1beta grew faster (240%, day 18, vs null-vector control LLC/neo; p < 0.01) and showed more abundant vasculature (250%, vs LLC/neo; p < 0.05), whereas LLC/IL-1beta cells, LLC/neo cells, and wild-type LLC cells did not show any significant difference in the growth rate in vitro. As compared with LLC/neo cells, LLC/IL-1beta cells secreted 2-fold the amount of vascular endothelial growth factor and >10-fold the amount of macrophage-inflammatory protein-2 (CXCL2), one of whose main functions is angiogenesis. Although LLC/IL-1beta itself did not secrete hepatocyte growth factor (HGF), the tumor derived from LLC/IL-1beta cells also contained a >4-fold higher concentration of HGF, another angiogenic factor. In situ hybridization of HGF mRNA in LLC/IL-1beta tumor sections demonstrated that stromal fibroblasts and infiltrating cells overexpressed HGF mRNA. Moreover, when cultured in the presence of HGF in vitro, LLC/IL-1beta cells secreted even larger amounts of vascular endothelial growth factor and macrophage-inflammatory protein-2. The antiangiogenic agent TNP-470 and anti-CXCR2 Ab inhibited the tumor growth of LLC/IL-1beta cells in vivo. These results indicated that secreting IL-1beta into the tumor milieu induces several angiogenic factors from tumor and stromal cells and thus promotes tumor growth through hyperneovascularization.
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PMID:Proinflammatory cytokine IL-1 beta promotes tumor growth of Lewis lung carcinoma by induction of angiogenic factors: in vivo analysis of tumor-stromal interaction. 1207 78

I examined the effects of carp oil, oleic acid, linoleic acid and linolenic acid on tumor growth and metastasis to the liver in mice implanted intrasplenically with highly metastatic Lewis lung carcinoma (LLC) tumors. Carp oil (0.1 or 0.2 mL per mouse) significantly reduced tumor growth and metastasis to the liver. Carp oil at 100 or 1000 mg/L inhibited the DNA synthesis in LLC cells, the capillary-like tube formation of human dermal microvascular endothelial cells (HMVEC) at 1000 mg/L and the adherence of LLC cells to HMVEC at 10 to 1000 mg/L (in vitro). Carp oil (0.2 mL per mouse) inhibited the angiogenesis induced by Matrigel supplemented with vascular endothelial growth factor (VEGF) and heparin (in vivo). Antitumor and antimetastatic actions of carp oil might be partly attributable to the inhibition of DNA synthesis in LLC cells and angiogenesis through the inhibition of the adherence of LLC cells to the microvascular endothelium. Oleic acid (0.1 or 0.2 mL per mouse) significantly inhibited the metastasis to the liver, but it had no effect on the primary solid-tumor growth. Oleic acid inhibited the angiogenesis in both in vitro and in vivo models. Oleic acid at 1000 micromol/L inhibited the DNA synthesis in LLC cells but did not affect the DNA synthesis in HMVEC. These inhibitory actions of oleic acid may be attributable to the inhibition of angiogenesis induced by the tumor. Linoleic acid and linolenic acid had no effect on tumor growth or metastasis to the liver.
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PMID:Carp oil or oleic acid, but not linoleic acid or linolenic acid, inhibits tumor growth and metastasis in Lewis lung carcinoma-bearing mice. 1209 95

Apoptosis induction is a promising approach for cancer gene therapy. Bax is a death-promoting member of the Bcl2 family of genes that are intimately involved in apoptosis. Overexpression of BAX protein can accelerate cell death by homodimers that promote apoptosis in a variety of cancer cell lines. The cytotoxic effect of BAX was evaluated in vitro by a recombinant adenovirus system expressing the human BAX gene under control of human vascular endothelial growth factor (VEGF) promoter element (AdVEGFBAX). Overexpression of BAX in human lung carcinoma cells resulted in apoptosis induction, caspase activation, and cell growth suppression, none of which were observed in BEAS-2B normal human bronchial epithelial cells that do not overexpress VEGF under normoxic conditions. To examine the hypoxia responsiveness of the VEGF promoter, lung cancer cells were transiently exposed to hypoxia; this treatment increased enhanced green fluorescent protein (EGFP) expression after AdVEGFEGFP infection in both normal and cancer cell lines, and enhanced apoptosis and decreased the number of surviving cancer cells compared with the Ad/BAX plus Ad/Cre binary adenoviral system. These results suggest a possible therapeutic application of cancer-specific expression of the pro-apoptotic Bax gene driven by the VEGF promoter.
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PMID:Adenovirus-mediated transfer of BAX driven by the vascular endothelial growth factor promoter induces apoptosis in lung cancer cells. 1216 Nov 85

Data obtained from multiple sources indicate that no single mechanism can explain the resistance to chemotherapy exhibited by non-small cell lung carcinomas. The multi-factorial nature of drug resistance implies that the analysis of comprising expression profiles may predict drug resistance with higher accuracy than single gene or protein expression studies. Forty cellular parameters (drug resistance proteins, proliferative, apoptotic, and angiogenic factors, products of proto-oncogenes, and suppressor genes) were evaluated mainly by immunohistochemistry in specimens of primary non-small cell lung carcinoma of 94 patients and compared with the response of the tumours to doxorubicin in vitro. The protein expression profile of non-small cell lung carcinoma was determined by hierarchical cluster analysis and clustered image mapping. The cluster analysis revealed three different resistance profiles. The frequency of each profile was different (77, 14 and 9%, respectively). In the most frequent drug resistance profile, the resistance proteins P-glycoprotein/MDR1 (MDR1, ABCB1), thymidylate-synthetase, glutathione-S-transferase-pi, metallothionein, O6-methylguanine-DNA-methyltransferase and major vault protein/lung resistance-related protein were up-regulated. Microvessel density, the angiogenic factor vascular endothelial growth factor and its receptor FLT1, and ECGF1 as well were down-regulated. In addition, the proliferative factors proliferating cell nuclear antigen and cyclin A were reduced compared to the sensitive non-small cell lung carcinoma. In this resistance profile, FOS was up-regulated and NM23 down-regulated. In the second profile, only three resistance proteins were increased (glutathione-S-transferase-pi, O6-methylguanine-DNA-methyltransferase, major vault protein/lung resistance-related protein). The angiogenic factors were reduced. In the third profile, only five of the resistance factors were increased (MDR1, thymidylate-synthetase, glutathione-S-transferase-pi, O6-methylguanine-DNA-methyltransferase, major vault protein/lung resistance-related protein).
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PMID:Protein expression profiles indicative for drug resistance of non-small cell lung cancer. 1217 90

Tumor tissues include malignant cells and a stroma made up of mainly inflammatory cells, endothelial cells, and fibroblasts. To differentiate the effects of treatment on angiogenic cytokine secretion in tumor tissue, exponential and stationary phase human CaKi-1 renal cell carcinoma cells, human SW2 small cell lung carcinoma cells, human umbilical vein endothelial cells (HUVECs), murine NIH-3T3 fibroblasts, and murine RAW264.7 macrophages were exposed to gemcitabine, paclitaxel, carboplatin, and the protein kinase Cbeta inhibitor LY317615, and secretion (24 h) of tumor necrosis factor-alpha, basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and transforming growth factor (TGF)-beta was determined by a Luminex FlowMetrix assay. After 72 h of exposure, exponential RAW, 3T3, and SW2 cells were sensitive to gemcitabine; exponential and stationary SW2 and HUVECs were sensitive to paclitaxel; and exponential and stationary HUVECs were most sensitive to LY317615. None of the cells secreted detectable tumor necrosis factor-alpha. Generally, exponential cells secreted higher levels of cytokines than stationary cells (stationary cells secreted approximately 10 times less TGF-beta). Only malignant cells secreted VEGF (80-300 pg/10(6) cells). VEGF secretion by exponential SW2 cells decreased in an anticancer agent concentration-dependent manner. Every cell type secreted TGF-beta (40-700 pg/10(6) cells). Exponential 3T3, RAW, CaKi-1, and SW2 cells secreted the most TGF-beta, and levels did not decrease with treatment. Only CaKi-1, SW2, and HUVECs secreted bFGF (0.5-50 pg/10(6) cells). CaKi-1 cells increased secretion of bFGF with therapy. Although malignant cells alone secreted VEGF, stromal cells secreted TGF-beta and bFGF at levels comparable with or greater than malignant cells and thus may be important contributors to tumor growth and progression.
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PMID:An in vitro tumor model: analysis of angiogenic factor expression after chemotherapy. 1235 73

Hypoxia is generally detected in central regions of solid tumors and regulates a variety of transcription factors including hypoxia-inducible factor-1 (HIF-1). HIF-1 plays a pivotal role in cellular response to low oxygen concentration, such as angiogenesis in tumor. Here, we found that a histone deacetylase (HDAC) inhibitor, FK228, inhibits the induction and activity of HIF-1 in response to hypoxia. Moreover, FK228 significantly suppressed the induction of vascular endothelial growth factor (VEGF) under hypoxia, suggesting that FK228 contributes to the inhibition of tumor angiogenesis. In Lewis lung carcinoma model, FK228 also blocked angiogenesis induced by hypoxia. These results suggest that FK228 can downregulate hypoxia-responsive angiogenesis through suppression of HIF-1alpha activity.
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PMID:Inhibition of hypoxia-induced angiogenesis by FK228, a specific histone deacetylase inhibitor, via suppression of HIF-1alpha activity. 1248 May 50


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