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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclooxygenase (COX)-2, the inducible isoform of prostaglandin H synthase, has been implicated in the progression of human lung adenocarcinoma. However, the mechanism underlying COX-2's effect on tumor progression remains largely unknown. Lymphangiogenesis, the formation of new lymphatic vessels, has recently received considerable attention and become a new frontier of tumor metastasis research. Here, we study the interaction between COX-2 and the lymphangiogenic factor, vascular endothelial growth factor (VEGF)-C, in human lung cancer cells and their implication in patient outcomes. We developed an isopropyl-beta-D-thiogalactopyranoside-inducible COX-2 gene expression system in human lung adenocarcinoma CL1.0 cells. We found that VEGF-C gene expression but not VEGF-D was significantly elevated in cells overexpressing COX-2. COX-2-mediated VEGF-C up-regulation was commonly observed in a broad array of non-small cell lung cancer cell lines. The use of pharmacological inhibitors or activators and genetic inhibition by EP receptor-antisense oligonucleotides revealed that prostaglandin EP(1) receptor but not other prostaglandin receptors is involved in COX-2-mediated VEGF-C up-regulation. At the mechanistic level, we found that COX-2 expression or prostaglandin E(2) (PGE(2)) treatment could activate the HER-2/Neu tyrosine kinase receptor through the EP(1) receptor-dependent pathway and that this activation was essential for VEGF-C induction. The transactivation of HER-2/Neu by PGE(2) was inhibited by way of blocking the Src kinase signaling using the specific Src family inhibitor, PP1, or transfection with the mutant dominant negative src plasmid. Src kinase was involved in not only the HER-2/Neu transactivation but also the following VEGF-C up-regulation by PGE(2) treatment. In addition, immunohistochemical staining of 59 lung adenocarcinoma specimens showed that COX-2 level was highly correlated with VEGF-C, lymphatic vessels density, and other clinicopathological parameters. Taken together, our results provided evidence that COX-2 up-regulated VEGF-C and promotes lymphangiogenesis in human lung adenocarcinoma via the EP(1)/Src/HER-2/Neu signaling pathway.
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PMID:Cyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma. 1474 69

Lung cancer is very frequent and associated with a high mortality. In the last 25 years therapeutic progress have been limited and do not allow a 5 year global survival rate exceeding to 13-14%. Tumor biology permits a better comprehension of cancerization mechanisms and offers hope of new treatments with targeted therapies which would be specific of cancer cells and so more efficient and less toxic. Epidermal growth factor (EGF) pathway and its receptor (EGFR) expressed by most lung cancer cells is the most successfully completed example. The bond of EGF with its receptor stimulates tyrosine kinase domain of EGFR and allows transduction of an activating signal. Inhibition of this signaling pathway stops tumor growth. Several agents are in development, from preclinical studies to phase III trials. It is a matter of humanized monoclonal antibodies, such as C225 (cetuximab), targeted against EGFR, or small molecules inhibiting tyrosine kinase activity of EGFR including ZD1839 (Iressa), OS1774 (Tarceva) or CI1033, and last antisense oligonucleotides. Antibodies and small molecules are well tolerated and are responsible for limited amount of side effects, mostly cutaneous toxicity and diarrhoea. Antitumor activity has been observed in monotherapy reaching up to 25% of clinical responses in the best series. EGFR inhibition seems to be also promising in combination with chemotherapy according to the synergy observed in preclinical studies and response rate up to 50% have been reported. But phase III studies have been disappointing and additional studies are warranted before consideration for a current daily practice, mostly that severe secondary effects were reported with pulmonary toxicities. In particular it remains to explain why clinical responses do not appear correlated with EGFR expression.
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PMID:[Therapeutic implications of epidermal growth factor receptor in lung cancer]. 1476 45

HER2 is reported to be overexpressed in 20% of cases of non-small-cell lung cancer (NSCLC), principally adenocarcinoma. Trastuzumab is a monoclonal antibody against HER2 that, when combined with a taxane, improves survival compared with chemotherapy alone in advanced breast cancer. In view of these observations, we conducted a phase II HER2 screening and efficacy trial of trastuzumab plus weekly docetaxel in cases of advanced NSCLC in which primary platinum-based therapy had failed. Patients with advanced or metastatic NSCLC were screened for HER2 overexpression by immunohistochemistry. Patients with HER2-positive tumors (2+ or 3+) were initially randomized to either single-agent trastuzumab or docetaxel. After completing 2 treatment cycles, all patients went on to receive the trastuzumab/docetaxel combination regardless of response to the single agents. Treatment consisted of docetaxel 30 mg/m2 weekly for 6 weeks followed by a 2-week break and trastuzumab 4 mg/kg intravenously on week 1 followed by 2 mg/kg per week thereafter. Cycle length was 8 weeks. Sixty-nine patients with NSCLC (33 men, 36 women) were screened between August 1999 and March 2001. Only 13 patients (19%) had HER2-positive disease; all 13 enrolled in the efficacy trial. Of 9 patients receiving docetaxel alone, 1 partial response (PR) was seen. None responded to trastuzumab alone. The overall outcomes to the sequence of single-agent therapy followed by combination therapy included a PR rate in 8% of cases, stable disease in 23%, progression in 46%, and nonassessable disease in 23%. Estimated event-free and overall survival times were 4.3 and 5.7 months, respectively. Treatment was well tolerated. The screening component of this trial demonstrated that the target population for trastuzumab therapy in NSCLC is relatively small. Because of the limited clinical activity of trastuzumab-based therapy in this cohort and the similar disappointing reports from other studies of trastuzumab in NSCLC, this trial was closed to further accrual. In view of the limited target population for HER2 inhibition, future efforts and resources should be directed toward molecular targets other than HER2 in NSCLC.
Clin Lung Cancer 2004 Jan
PMID:Trastuzumab plus docetaxel in HER2/neu-positive non-small-cell lung cancer: a California Cancer Consortium screening and phase II trial. 1496 75

Research over the past decade has led to an increased understanding of the pathophysiology of lung cancer. The HER2/neu receptor is a member of the ErbB family of signaling-transduction receptors and appears to play a major role in the development of lung cancer as well as many other solid tumors. HER2/neu is overexpressed in 16% to 57% of patients with non-small cell lung cancer (NSCLC) and studies have shown that HER2/neu overexpression imparts a poor prognosis in both resected and advanced NSCLC, as it does in breast cancer. Trastuzumab, a humanized monoclonal antibody that recognizes the HER2/neu protein receptor, has been approved by the US Food and Drug Administration for patients with HER2/neu-positive metastatic breast cancer. In NSCLC preclinical studies, marked synergistic growth inhibition occurred when standard cytotoxic chemotherapy was combined with trastuzumab in HER2/neu-expressing cell lines. In the clinical setting, trastuzumab has proven safe and feasible in combination with cytotoxic chemotherapy in both single-institution and multi-institutional cooperative group studies. Unlike the experience in advanced breast cancer, cardiac toxicity is a marginal concern in this population. However, to date, clinical studies with trastuzumab in patients with NSCLC have not shown a demonstrable advantage for the majority of patients.
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PMID:The role of HER2/neu expression and trastuzumab in non-small cell lung cancer. 1498 84

Lung cancer is the leading cause of death worldwide. Current treatment modalities, including chemotherapy, radiotherapy and surgery, provide only limited improvement in the natural course of this disease. Therefore, the development of new therapeutic strategies is highly awaited. This review focuses on recent achievements on a novel class of anticancer drugs targeting the EGFR (Epidermal Growth Factor Receptor). The EGFR family is a group of four structurally similar growth factor receptors with tyrosine-kinase activity (EGFR, HER2/neu, ErbB-3, ErbB-4), which dimerize upon binding with a number of ligands, including EGF (Epidermal Growth Factor) and TGF (Transforming Growth Factor), allowing downstream transduction of mitogenic signals. Overexpression of EGFR and HER2 is frequently found in non-small-cell lung cancer (NSCLC), which accounts for over 80% of all malignant lung tumors, and has been associated with a worse clinical outcome. New agents developed to inhibit EGFR function include monoclonal antibodies and small-molecule receptor tyrosine-kinase inhibitors. In this review, results of most recent clinical with EGFR inhibitors including monoclonal antibodies, such as Trastuzumab (Herceptin), IMC-C225 (Cetuximab) and others (ABX-EGF, EMD 72000), and tyrosine-kinase inhibitors, such as ZD1839 (Gefitinib, Iressa), OSI-774 (Erlotinib, Tarceva) and others (CI-1033, GW2016), are summarized. In particular, final results of phase II (IDEAL 1 and 2) and III (INTACT 1 and 2) studies of ZD1839 are reported. In IDEAL trials (ZD1839 single agent in patients pre-treated with chemotherapy) there was clear evidence of tumor regression, symptoms improvement and overall clinical benefit, whereas in the two INTACT trials (ZD1839 in combination with standard platinum-based chemotherapy in chemo-naive patients) ZD1839 did not improve either survival or other clinical endpoints. Possible explanations for these contradictory results and future perspectives are discussed.
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PMID:Epidermal growth factor receptor inhibitors: a new prospective in the treatment of lung cancer. 1503 19

Vascular endothelial cell growth factor (VEGF) plays an important role in the processes of angiogenesis. Angiogenesis appears to be essential for the growth of solid tumors and their metastasis. VEGF plays a principal role in tumor angiogenesis. To identify a compound that inhibits the binding of VEGF to its receptor, we used a high-throughput screening method and found that oxydibenzoic acid derivatives inhibited VEGF binding to its receptors. Among the active compounds, 5-[3-[4-(octadecyloxy)phenyl]propionylamino]-2,4'-oxydibenzoic acid (VGA1102) was selected based on its potent binding inhibitory activity. VGA1102 inhibited [(125)I]VEGF binding to both of two VEGF receptor-transfected cell lines, NIH-Flt-1 and NIH-KDR/Flk-1, in a concentration-dependent manner, with IC(50) values of 0.66+/-0.07 and 0.61+/-0.16 micro M, respectively. VGA1102 (10 micro M) exhibited inhibitory activity against VEGF-induced receptor autophosphorylation. VGA1102 also inhibited VEGF-induced growth of rat liver sinusoidal endothelial cells (IC(50)=0.89+/-0.16 micro M) as well as VEGF-induced tube formation of HUVEC in vitro. VGA1102 reduced intradermal VEGF-induced vascular permeability in guinea pigs. Treatment with VGA1102 (50 mg/kg, i.p., days 0-20) significantly increased the lifespan of MM2-bearing mice with an increase in lifespan of >195.8%, and all such mice were long-term survivors on day 71. Furthermore, VGA1102 (50 mg/kg, i.p.) administered daily suppressed the growth of nude mice transplanted with LC-6 human non-small-cell lung cancer. These results suggest that VGA1102 inhibits VEGF function resulting in inhibition of tumor angiogenesis, which led to suppression of growth of human tumors transplanted into nude mice.
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PMID:A novel low molecular weight VEGF receptor-binding antagonist, VGA1102, inhibits the function of VEGF and in vivo tumor growth. 1506 56

The incidence of lung cancer is increasing throughout the world and is the most common cause of cancer-related death. Early detection followed by surgery has a reasonable, curative potential, but 30-50% of patients experience relapses. The immunohistochemical expressions of HER-2, EGFR and COX-2 were investigated in 53 resected non-small cell lung carcinomas and correlated to microvessel density and clinical data. HER-2, EGFR and COX-2 overexpressions were demonstrated in 15%, 30% and 40% of the tumours, respectively. In adenocarcinomas, HER-2 and COX-2 overexpression were more common, whereas in squamous cell carcinomas, EGFR overexpression was more common. COX-2 expression correlated with HER-2 expression (p = 0.002), and demonstrated a trend towards a correlation with microvessel density (p = 0.10). None of the markers alone had any impact on survival. However, HER-2+/EGFR- tumours proved to have a poor prognosis. In conclusion, adjuvant treatment with HER-2 antagonists might be a future treatment option in resected non-small cell lung cancer patients, especially when HER-2 is overexpressed without a concomitant overexpression of EGFR.
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PMID:HER-2, EGFR, COX-2 expression status correlated to microvessel density and survival in resected non-small cell lung cancer. 1506 24

Gefitinib (Iressa, ZD1839), a quinazoline tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR), is approved for patients with advanced non-small cell lung cancer (NSCLC) in several countries including Japan. However, the mechanism of drug sensitivity to gefitinib is not fully understood. In this study, we examined the molecular basis of sensitivity to gefitinib using nine human lung cancer cell lines derived from NSCLC. PC9 was the most sensitive to gefitinib of the nine NSCLC cell lines when assayed either by colony formation or MTS assays. The various cell lines expressed different levels of EGFR, HER2, HER3, and HER4, but there was no correlation between levels of EGFR and/or HER2 expression and drug sensitivity. Phosphorylation of EGFR, protein kinase B/AKT (Akt), and extracellular signal-regulated kinase (ERK) 1/2 was inhibited by much lower concentration of gefitinib in PC9 cells than in the other eight cell lines under exponential growing conditions. About 80% of cell surface EGFR in PC-9 was internalized within 10 min, whereas only about 30-50% of the cell surface EGFR was internalized in more drug-resistant cell lines in 15-60 min. The present study is the first to demonstrate that sensitivity to growth inhibition by gefitinib in NSCLC cell lines under basal growth condition is associated with dependence on Akt and ERK1/2 activation in response to EGFR signaling for survival and proliferation and also that drug sensitivity may be related to the extent of EGF-induced down-regulation of cell surface EGFR.
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PMID:Sensitivity to gefitinib (Iressa, ZD1839) in non-small cell lung cancer cell lines correlates with dependence on the epidermal growth factor (EGF) receptor/extracellular signal-regulated kinase 1/2 and EGF receptor/Akt pathway for proliferation. 1507 90

Receptor tyrosine kinase genes were sequenced in non-small cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinib-insensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib.
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PMID:EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. 1573 72

The epidermal growth factor receptor (EGFR) is a member of the erbB family of tyrosine kinase receptors (RTK). The EGFR is involved in cell proliferation, metastasis and angiogenesis, and is expressed in a large proportion of epithelial tumours. The two main classes of EGFR inhibitors in clinical trials are the RTK inhibitors and the monoclonal antibodies. The clinical development of EGFR inhibitors has introduced new challenges to the design of phase I, II, and III trials. Both classes of agents can be safely administered at doses sufficient to inhibit the EGFR system. Receptor tyrosine kinase inhibitors have been extensively evaluated in non-small-cell lung cancer. In this setting, gefitinib has demonstrated activity in patients who fail initial chemotherapy. Monoclonal antibodies have been developed in combination with cytotoxic chemotherapy in several tumour types, most notably colorectal and head and neck cancer. The preliminary results suggest an increase in response rate and time to progression with the combination of cetuximab and chemotherapy in both disease models. Future issues in the development of EGFR inhibitors include the identification of biologic predictors of response, combination with other targeted agents, and their utilisation in earlier stage malignancies.
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PMID:Targeting the epidermal growth factor receptor. 1523 78


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