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)

Progression of solid tumors, including NSCLC, is associated with increase in MVC (microvessel count), as a measure of tumor angiogenesis resulting from an imbalance between angiogenic factors and inhibitors. However, since tumor angiogenesis is a multi-step process under the control of various molecules, the mechanism of angiogenesis has not been fully clarified. Interleukin (IL)-8 has been shown to have a potential angiogenic effect in vitro and in vivo, and is overexpressed in several human solid cancers. Among the various angiogenic factors, vascular endothelial growth factor (VEGF) has been shown to correlate with a high MVC and with adverse prognosis in several human cancers, including NSCLC. Alterations of p53 suppressor gene are the most common genetic changes found in malignant tumors; several studies examined the link between aberrant p53 and angiogenesis in lung cancer, but only a few studies report data regarding a relation between p53 mutations and IL-8 expression. In this study we observed a correlation between IL-8 mRNA expression, intratumoral MVC and VEGF mRNA expression levels; furthermore, an aberrant p53 status was related to IL-8 expression. However, in our samples IL-8 levels did not significantly affect prognosis of NSCLC; more studies are required to elucidate the precise role of IL-8 in a large series of patients with non-small cell lung carcinoma.
Lung Cancer 2005 Dec
PMID:Interleukin-8 in non-small cell lung carcinoma: relation with angiogenic pattern and p53 alterations. 1612 76

The treatment of lung cancer remains a significant challenge. Although chemotherapy remains the standard approach, a plateau has been reached in its efficacy. The development of novel targeted agents, particularly those targeting the epidermal growth factor receptor, has given us another approach. Developments with antiangiogenesis agents hold promise as new approaches in lung cancer therapy. Much of the work to date has focused on the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab. In this article we will focus on the tyrosine kinase inhibitors of the VEGF receptors. These compounds, including sunitinib (SU11248; Sutent), vatalanib (PTK787), ZD6474, AZD2171, GW786034, sorafenib (BAY 43-9006), CP-547,632, and AG013736, are still at an early stage of development. We present phase I data (and phase II/III data when available) of these compounds and discuss their potential development in the treatment of lung cancer.
Clin Lung Cancer 2005 Sep
PMID:Targeting angiogenesis with vascular endothelial growth factor receptor small-molecule inhibitors: novel agents with potential in lung cancer. 1615 17

Growth factor signals are propagated from the cell surface to intracellular processes that control critical functions such as growth, differentiation, angiogenesis, and inhibition of apoptosis via sequential kinase signaling. These kinases are receptor kinases, which are transmembrane proteins such as epidermal growth factor receptor or cytoplasmic kinases such as Src kinase. In malignancies, these signaling pathways are often exploited to optimize tumor growth and metastasis. Thus, they represent attractive targets for cancer therapy. This review will summarize current knowledge of the small-molecule multiple-kinase inhibitors in lung cancer therapy. These inhibitors generally hinder the phosphorylation of several protein kinases of membrane receptors, such as vascular endothelial growth factor receptors, platelet-derived growth factor receptors, the human epidermal growth factor receptor family, and cytoplasmic receptors such as c-Kit, Raf kinase, and FLT3. These inhibitors include ZD6474, SU11248, AEE 788, sorafenib, vatalanib, and AG-013736.
Clin Lung Cancer 2005 Sep
PMID:Targeting multiple signal transduction pathways in lung cancer. 1615 18

The endothelin (ET) system influences tumourigenesis and tumour progression by various mechanisms, including angiogenesis. The aim of this study was to determine whether the expression of endothelin-1 (ET-1) is related to the angiogenic phenomenon in lung cancer and whether it could be involved in its clinical behaviour. Expression of ET-1, endothelin-converting enzyme-1 (ECE-1) and endothelin-receptors ETA and ETB was examined in 201 non-small cell lung carcinoma (NSCLC) and corresponding normal tissues using real-time polymerase chain reaction (RT-PCR). Forty NSCLC were also analysed for vascular endothelial growth factor (VEGF) expression by a competitive-PCR approach to assess whether ET-1 expression was related to this angiogenic factor. A higher number of cases with ET-1, ECE-1 and ETA mRNA expression was observed in malignant lung tumours compared with normal lung tissues (45.7% versus 33% for ET-1 (P < 0.0001); 38.3% versus 16.5% for ECE-1 (P = 0.004); and 42.8% versus 28.5% for ETA (P < 0.0001)). On the other hand, ETB mRNA was higher in normal lung tissues than in tumour samples (58.5% versus 52.8% (P < 0.0001)). Immunohistochemical analysis was also performed in 78 cases, selected from among those with high ET-1 mRNA, to confirm the presence of ET-1 protein and to determine its distribution and localisation. Moreover, an interesting relationship was observed between ET-1 and VEGF mRNA levels (P = 0.02). At univariate analysis, clinical-pathological parameters, such as sex, nodal metastatic involvement and stage, and ET-1 expression were seen to be significant predictors of worse prognosis regarding both overall survival (P = 0.001, P = 0.0003, P = 0.001 and P = 0.03, respectively) and disease-free interval (P = 0.0005, P = 0.0007, P = 0.001 and P = 0.04, respectively). We conclude that ET-1 could be involved in angiogenic phenomena in NSCLC and may represent a further indicator of progression and poor prognosis in this type of cancer, with interesting therapeutic implications.
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PMID:Expression of endothelin-1 is related to poor prognosis in non-small cell lung carcinoma. 1629 24

With recent Food and Drug Administration approval of the anti-vascular endothelial growth factor (VEGF) antibody for the treatment of colon cancer, it may be possible to achieve similar progress in the treatment of locally advanced lung cancer. Antiangiogenic therapies in the clinic are a reality, and it is important to demonstrate that they can be used safely with conventional modalities, including radiation therapy (RT). Strategies under scrutiny in preclinical and clinical studies include the use of endogenous inhibitors of angiogenesis, use of agents that target VEGF and VEGF receptor signaling, targeting endothelial-related integrins during angiogenesis, and targeting the preexisting immature vessels growing within tumors (ie, vascular targeting). Regardless of the approach, it is necessary to address whether angiogenesis is a consistent phenomenon within the lung parenchyma around a cancer and a relevant target and whether inhibiting angiogenesis will improve current lung cancer therapies without increasing toxicity. Vascular-targeting agents (VTAs) are an interesting class of agents that have the potential to enhance RT, but their clinical promise has yet to be realized. In preclinical models, these agents selectively destroy the tumor vasculature, initiating a rapid centralized necrosis within established tumors. Characteristically, after treatment with VTAs, a rim of viable tumor cells remains at the periphery of the tumor, which remains well perfused and should therefore be relatively sensitive to radiation-induced cytotoxicity. This review will focus on VTAs in the treatment of lung cancer and includes a discussion of combination studies with RT in the laboratory and some of the hurdles in the clinical application of these agents.
Clin Lung Cancer 2005 Nov
PMID:Vascular-targeting agents and radiation therapy in lung cancer: where do we stand in 2005? 1635 11

Tumor cells in hypoxic areas of solid tumors are resistant to conventional chemotherapy and radiotherapy and thus are obstacles of cancer therapy. We report here the feasibility of applying hypoxia-regulated expression of diphtheria toxin A (DT-A) for killing hypoxic tumor cells. The expression vector was constructed to express DT-A fused with hypoxia-inducible factor-1alpha (HIF-1alpha) oxygen-dependent degradation (ODD) domain under the control of vascular endothelial growth factor gene promoter and contain erythropoietin mRNA-binding protein (ERBP)-binding sequence downstream of the DT-A/ODD sequence. In vitro ubiquitination assay showed that DT-A/ODD, but not DT-A, was ubiquitinated as efficient as HIF-1alpha under normoxic conditions in a von Hippel-Lindau- and oxygen-dependent manner. DT-A/ODD exhibited a comparable translation inhibitory activity to DT-A. ERBP-binding sequence was effective in stabilizing mRNA under hypoxic conditions in various cell types. Transfection of the vector expressing DT-A/ODD into high-metastatic Lewis lung carcinoma (3LL) A11 cells resulted in induction of apoptosis independently of hypoxia, probably due to its extreme toxicity. However, transfection of the vector expressing attenuated DT-A(W153F)/ODD or DT-A(H21A)/ODD resulted in a hypoxia-dependent induction of apoptosis. Liposomal gene transfer of the vector encoding DT-A(W153F)/ODD induced apoptosis in hypoxic, but not in normoxic, areas of solid tumors established by A11 variant cells with higher resistance to hypoxia-induced apoptosis and inhibited the growth of hypoxic tumors established by 3LL-P29 cells. These results suggest that hypoxia-regulated expression of attenuated DT-A(W153F)/ODD fusion protein is potentially of use for killing hypoxic tumor cells with minimizing the damage to normoxic normal tissues.
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PMID:Hypoxia-regulated expression of attenuated diphtheria toxin A fused with hypoxia-inducible factor-1alpha oxygen-dependent degradation domain preferentially induces apoptosis of hypoxic cells in solid tumor. 1635 73

The median survival time for advanced non-small cell lung cancer (NSCLC) remains poor, despite years of research into new chemotherapy combinations. Platinum-based chemotherapy has long been the standard of care for the initial treatment of advanced NSCLC. While no one particular platinum-based chemotherapy regimen is definitely superior to the others (as demonstrated in the Eastern Cooperative Oncology Group's E1594 trial), three randomized phase III trials (the Southwest Oncology Group 9509, Italian Lung Cancer Project, and TAX326 trials) have recently demonstrated that taxane-platinum doublets are better tolerated than a combination of vinorelbine and cisplatin (VC). Moreover, a combination of docetaxel and cisplatin produced superior survival and quality of life than VC in the TAX326 study. Nonplatinum combinations, such as a taxane-gemcitabine doublet, appear promising and better tolerated than their platinum-based comparators in other studies. Efforts to evaluate chemotherapy specifically in elderly patients and in those with poor performance status (PS) have increased. Single-agent chemotherapy has been safely administered to these populations, but platinum-based doublet therapy may also be feasible in both elderly patients and patients with PS scores of 2. The addition of the monoclonal antibody against vascular endothelial growth factor, bevacizumab, to standard chemotherapy for patients with non-squamous cell advanced NSCLC significantly extended median survival in the E4599 randomized trial. Each incremental advance demonstrates that progress can be made in first-line treatment of advanced NSCLC.
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PMID:Optimizing first-line treatment options for patients with advanced NSCLC. 1636 66

The treatment of advanced-stage lung cancer continues to be challenging. Cytotoxic chemotherapy doublets have modestly improved survival and have emphasized more quality of life issues. Many novel targeted agents are in clinical development and could have potential to treat patients with lung cancer whose tumors are refractory to standard cytotoxic regimens. Targeting the epidermal growth factor receptor as well as the vascular endothelial growth factor pathways appears promising. Combining these targeted agents with chemotherapy might help improve overall efficacy. Docetaxel is an active chemotherapeutic agent that has been studied in combination with multiple biologic agents. With continued study, optimizing these combinations for specific patient populations will be the key to improving overall efficacy.
Clin Lung Cancer 2005 Dec
PMID:Novel combinations with docetaxel in the treatment of non-small-cell lung cancer. 1638 41

Angiogenesis is required for lung cancer growth, which is mediated by various growth factors such as vascular endothelial growth factor (VEGF). Increases in VEGF and angiogenesis have been correlated with poor prognosis and survival in patients with lung cancer. In addition, recent reports show that estradiol and nicotine play important roles in lung tumor initiation and progression. In this report, we demonstrate that estradiol and nicotine exposure enhances the growth of A549 bronchioloalveolar carcinoma xenografts in mice through the stimulation of cell proliferation, VEGF secretion and angiogenesis. We detect a four-fold increase in microvascular density in tumors from mice exposed to estradiol and nicotine compared to control tumors resulting in an increase in tumor growth. Intriguingly, the effects on angiogenesis and tumor growth by the combination of agents were additive when compared to either agent alone. Furthermore, estradiol promotes VEGF secretion from various non-small cell lung carcinoma (NSCLC) cells and this effect is augmented by nicotine in a tumor xenograft model. These results indicate that aside from their roles in promoting cell proliferation, estradiol and nicotine appear to have additive effects on the induction of angiogenesis through the stimulation of VEGF secretion during NSCLC progression.
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PMID:Estradiol and nicotine exposure enhances A549 bronchioloalveolar carcinoma xenograft growth in mice through the stimulation of angiogenesis. 1639 87

Chemotherapy extends life and provides symptom palliation for patients with advanced non-small cell lung cancer (NSCLC). Numerous trials have been conducted that evaluate a variety of doublet regimens, but the majority of trials have found equal efficacy among the treatment arms. Indeed, a plateau appears to have been reached with respect to survival associated with traditional cytotoxic drug regimens. It was initially hoped that the addition of novel targeted agents to conventional chemotherapy would produce significant survival benefits for patients with advanced NSCLC; however, most trials have failed to show such a benefit. There is no survival benefit associated with adding erlotinib or gefitinib to a chemotherapy regimen, although there is a significant improvement in survival associated with erlotinib monotherapy in the second- and third-line advanced disease setting. In contrast, the results of E4599 clearly demonstrate that the addition of bevacizumab to paclitaxel-carboplatin chemotherapy extends survival in a select group of patients with non-squamous cell NSCLC. E4599 also represents a rational approach to drug development that could be modeled in other trials, namely, the use of a large, well designed, randomized trial prior to beginning a traditional phase II approach. This strategy can lead to the identification of subgroups most likely to benefit, as well as those that might experience increased toxicity, such as patients with squamous cell carcinoma treated with bevacizumab. Another approach to optimizing targeted therapy involves selecting a chemotherapy regimen with the greatest potential for synergy based on preclinical modeling. Because docetaxel has been shown to prolong survival in second-line treatment, a number of novel agents have been combined with docetaxel in order to improve efficacy. Alternatively, investigators have sought to combine novel agents with either carboplatin-paclitaxel or cisplatin-gemcitabine in first-line treatment. A number of trials are underway that combine these agents with inhibitors of the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and the proteasome, as well as COX2 inhibitors, and novel immunomodulators.
Lung Cancer 2005 Dec
PMID:Optimizing chemotherapy and targeted agent combinations in NSCLC. 1655 19


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