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

Cell adhesion is important in the regulation of cell proliferation, migration, survival, and apoptosis. The major components of cell adhesion are the cadherin family of proteins, alpha-, beta- and gamma-catenins, and cytoskeletons. In addition, beta-catenin, when associated with adenomatous polyposis coli (APC) protein, an oncosuppressor, is implicated in the regulation of beta-catenin/APC-related signaling pathways. To examine the correlation between impairment of cell adhesion events and apoptosis, we used human non-small-cell lung cancer H460 and H520 cell lines as models to determine whether paclitaxel-induced apoptosis is associated with disruption of the components of cell adhesion and their functions. Paclitaxel treatment resulted in cells rounding up and losing contact with their neighboring cells, suggesting that the drug does indeed affect cell adhesion and related events. Western blot analysis revealed that paclitaxel caused a time- and concentration-dependent cleavage of beta-catenin, gamma-catenin, and APC protein, but not alpha-catenin or E-cadherin. These cleavages of beta-catenin and gamma-catenin were apoptosis-dependent, not mitosis-dependent. Paclitaxel treatment led to the proteolysis and activation of caspase-3 and -7, but not caspase-1. Furthermore, paclitaxel-induced apoptosis and cleavage of beta-catenin and gamma-catenin were inhibited by the pan-caspase inhibitor Z-VAD-FMK and partially inhibited by the caspase-3 inhibitor Z-DEVD-FMK but were not affected by the caspase-1 inhibitor AC-YVAD-CMK. Although the pan-caspase inhibitor blocked the cleavage of beta-catenin as well as DNA fragmentation, it did not affect paclitaxel-induced M-phase arrest and only partially prevented cell-growth inhibition. Biochemical studies revealed that cleaved beta-catenin was detected only in the Triton X-100 insoluble fraction, suggesting that it might localize in nuclear and/or membrane structures. Interestingly, the paclitaxel-induced beta-catenin fragment lost its ability to bind to E-cadherin, alpha-catenin, or APC protein and to serve as a substrate for tyrosine kinase. All our data demonstrate that the caspase-mediated cleavage of beta-catenin, gamma-catenin, and APC protein might contribute to paclitaxel-induced apoptosis.
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PMID:Disruption of cell adhesion and caspase-mediated proteolysis of beta- and gamma-catenins and APC protein in paclitaxel-induced apoptosis. 1117 55

Adhesion molecules are involved in intracellular signaling in various physiological and pathological processes including metastasis and growth of tumor cells. Tumor cells interact with various host cells as well as with extracellular matrices through certain adhesion molecules such as integrins. We here propose that stimulation of beta1 integrin reduces intercellular adhesion molecule (ICAM)-1-mediated interaction of lung cancer cells with CTLs. This concept is based on the following findings: (a) engagement of beta1 integrins on certain lung cancer cells by a specific antibody or by ligand matrices such as fibronectin and collagen markedly reduced ICAM-1 expression on the cell surface and induced sICAM-1; (b) down-regulation of ICAM-1 by stimulation of beta1 integrins was abrogated by tyrosine kinase inhibitors or by transfection of dominant negative truncations of focal adhesion kinase (FAK); (c) engagement of beta1 integrins also reduced ICAM-1-dependent adhesion of lung cancer cells to T cells, a process completely inhibited by tyrosine kinase inhibitors and by transfection of dominant negative forms of FAK; and (d) stimulation of beta1 integrins prevented killing of lung cancer cells by autologous CTLs. In malignant tumors, cancer cells, including lung cancer cells, are surrounded by extracellular matrix proteins such as fibronectin and collagen. This suggests that the engagement of beta1 integrins by matrix proteins potentially occurs in cancer cells in vivo and that continuous stimulation via beta1 integrins reduces ICAM-1-expression, ICAM-1-mediated adhesion of cancer cells to CTLs and their killing by CTLs. Our results suggest that such processes can lead to the escape of lung cancer cells in vivo from immunological surveillance.
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PMID:Stimulation of beta1 integrin down-regulates ICAM-1 expression and ICAM-1-dependent adhesion of lung cancer cells through focal adhesion kinase. 1128 Jul 62

Small-cell lung cancer (SCLC) carries a bad prognosis despite good initial response to chemotherapy. It is therefore important to identify molecular markers that influence survival as potential new therapeutic targets. In our study, expression of the tyrosine kinase c-erbB-2 (HER2/neu) receptor in tumor tissues of 107 consecutive newly diagnosed patients with primary SCLC was quantified using a monoclonal antibody directed against the c-terminal domain of c-erbB-2. A clear-cut positive expression of c-erbB-2 was observed in 13% of patients. Surprisingly, c-erbB-2 was an independent prognostic factor (RR = 2.16; p = 0.014) when a proportional-hazard model was adjusted to stage (limited vs. extensive disease) and performance status (WHO I-IV), the most relevant clinical parameters. Similarly, a significant association between c-erbB-2 and survival was obtained if a larger number of clinical parameters were included into the analysis, namely response to chemotherapy, TNM stage, lactate dehydrogenase (LDH), neuron-specific enolase (NSE), gender and age (p = 0.033). Interestingly, c-erbB-2 expression was more relevant for patients with advanced tumors. In the subgroup of patients with bad performance status (WHO II-IV), median survival of patients with undetectable c-erbB-2 expression was 274 days compared with only 23 days for patients with clear-cut positive c-erbB-2 immunohistochemistry (p = 0.0031; log-rank test). Similar results were obtained for patients with extensive disease (p = 0.028) and high TNM stages (T>2 or N>1 or M1; p < 0.068, all comparisons). In contrast, c-erbB-2 expression was not associated with survival in patients with limited disease (p = 0.97), low TNM stages (p > 0.56, all comparisons) and good performance status (p = 0.97). In conclusion, c-erbB-2 is expressed in more than 10% of SCLC. Expression of c-erbB-2 is an independent prognostic factor of survival. The effect of c-erbB-2 expression seems to become more important in advanced stages of the disease. Since c-erbB-2 is a therapeutical target in other types of cancer, further studies to identify the role of c-erbB-2 in SCLC are clearly warranted.
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PMID:c-erbB-2 expression in small-cell lung cancer is associated with poor prognosis. 1130 79

Vascular endothelial growth factor (VEGF) is known to be a highly specific mitogen for endothelial cells through two high-affinity tyrosine kinase receptors, VEGFR-1 and VEGFR-2, which are almost specifically expressed in endothelial cells. However, recent findings showed that VEGF receptors may also expressed by nonendothelial cells, especially by tumor cells. To further understand the functional expression of VEGF receptors by nonendothelial cells, our preliminary screening detected the expression of VEGFR-2 in 115 different paraffin-embedded cancer specimens including 35 cases of bladder tumor, 30 cases of breast cancer, 25 cases of intestinal cancer, and 25 cases of lung cancer with immunohistochemistry. The results showed that VEGFR-2 was widely expressed in different tumor tissues. By reverse transcription PCR, NCI-H23, NCI-H460, MGC803, MDA-MB-231, 293, and MCF7 cells were evaluated for the mRNA expression of both VEGF and VEGFR-2. The data indicated that all these tumor cell lines expressed detectable amounts of VEGF mRNA, but only 293, MCF7, and MGC803 cells coexpressed VEGFR-2. Immunoblot analysis also demonstrated the expression of VEGFR-2 at protein level. We further demonstrate that exogenous rhVEGF(165) could stimulate cell growth in MGC803, a tumor cell line derived from gastric adenocarcinoma, in a dose- and time-dependent manner. Furthermore, the antibodies against rhVEGF(165) and VEGFR-2 could block rhVEGF(165)-mediated proliferation of MGC803 cells. These unexpected results provided direct evidence that VEGF may act as an autocrine growth factor to induce the proliferation of gastric adenocarcinoma cells as well as tumor angiogenic cells, thus suggesting a promising tumor therapeutic application based upon the VEGF system.
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PMID:Vascular endothelial growth factor: acting as an autocrine growth factor for human gastric adenocarcinoma cell MGC803. 1151 Oct 87

In the last decade combined modality treatment approaches contributed to the progress of therapy in locally advanced non-small cell lung cancer. With this management strategies younger patients (<70 years) with locally advanced disease and a good performance status (ECOG 0,1) have survival benefits compared to sole locoregional treatment. Further development of these treatment concepts is warranted. To adopt optimal tailored therapy to prognostic consistent patient groups exact staging of disease is mandatory. Moreover, refinements of the staging system would be helpful to identify in defined anatomical stages, patient subgroups who will benefit from systemic treatment options different from chemotherapy (i.e. tyrosine kinase-inhibition of the epidermal growth factor receptor family, anti-angiogenic treatment). The current status of developing treatment strategies in locally advanced non-small cell lung cancer is discussed.
Lung Cancer 2001 Sep
PMID:Development of treatment strategies in locally advanced non-small cell lung cancer (take home messages). 1157 13

Tyrosine kinases are enzymes that regulate mitosis, differentiation, migration, neovascularization, and apoptosis. Their spectrum and association with specific malignancies offer multiple targets for therapeutic intervention. Chronic myelogenous leukemia (CML) represents an ideal target for a therapy using a selective inhibitor of the BCR-ABL tyrosine kinase. The 2-phenylpyrimidine derivative STI571 was rationally designed to inhibit ABL and BCR-ABL tyrosine kinase activities through competitive ATP-binding pocket interactions. Phase II data demonstrate hematologic and cytogenetic responses in interferon refractory chronic-phase, accelerated-phase and blast crisis patients. However, long-term observation is needed to confirm that response data result in prolongation of survival. STI571 is being studied in other malignancies, including leukemias characterized by expression of alternate molecular forms of BCR-ABL and those expressing protein tyrosine kinases with ATP-binding pockets structurally similar to ABL, e.g. c-kit and PDGF-R. Gastrointestinal stromal tumor (GIST) cells overexpress the stem cell factor receptor CD117, the product of the proto-oncogene c-kit. Inhibition of c-kit in vivo results in an immediate metabolic change of the tumor cells, detectable by positron emission tomography. Since c-kit overexpression is inhibited in small-cell lung cancer cell lines, a study with STI571 as second-line therapy of c-kit-positive small-cell lung cancer is in progress. Clinical studies are ongoing in malignancies associated with an enhanced activity of the PDGF-R, such as highgrade glioma, prostate cancer and leukemias with rearrangements of PDGF-R. The development of selective tyrosine kinase inhibitors is considered a promising approach for the design of new drugs. Clinical responses to STI571 in various malignancies may stimulate greater interest in the clinical use of tyrosine kinase inhibitors.
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PMID:[Selective inhibition of tyrosine kinases - a new therapeutic principle in oncology]. 1160 Aug 16

Is any one combination therapy for metastatic non-small cell lung cancer (NSCLC) superior to other regimens for metastatic NSCLC? The answer is "probably no." More than 4,000 patients with advanced NSCLC participated in randomized trials presented at the 37th Annual Meeting of the American Society of Clinical Oncology. TAX326 was the only study in which the investigational arm (cisplatin/docetaxel) showed a statistically significant difference in survival compared with the reference standard (cisplatin/vinorelbine). We did learn, however, that what we administer may make some difference: cisplatin might be superior to carboplatin, and patients treated with nonplatinum chemotherapy regimens have a trend toward poorer survival than those who receive platinum doublets. Although there is still no clear best regimen for advanced NSCLC, we may now know how much chemotherapy to give: a randomized study presented found that four cycles produces as much survival benefit as treating until progression. The most significant abstracts presented at this year's lung cancer session involved the use of novel agents with unique mechanisms of action. The median survival in the large, randomized trials of chemotherapy in advanced NSCLC remains a bleak 9 months. ISIS 3521, an antisense oligonucleotide that targets protein kinase C, was found to produce a near doubling of survival when combined with carboplatin and paclitaxel. OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, was shown to have impressive single agent activity in the second-line treatment of lung cancer. The future of lung cancer therapy will involve combining these novel agents with active chemotherapy regimens in an effort to improve outcome. While we appear to have reached a plateau in what we can accomplish with various combinations of cytotoxic chemotherapy in metastatic NSCLC, in locally-advanced disease new chemotherapy combinations can achieve remarkable results when combined with radiation therapy. The Southwest Oncology Group presented unprecedented phase II data on the use of cisplatin and etoposide with concurrent radiation therapy followed by consolidation docetaxel in patients with stage IIIB NSCLC.
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PMID:Lung cancer. 1167 18

The epidermal growth factor receptor is overexpressed in a majority of non-small cell lung cancers and has been associated with a poor prognosis. Preclinical studies have shown that ZD1839, an oral anilinoquinazoline, targets the epidermal growth factor receptor-associated tyrosine kinase, reversibly inhibiting critical downstream signaling and resulting in cancer cell growth arrest. Potent antitumor effects have been observed in human lung tumor xenograft models. Preclinical studies have shown additive to synergistic effects when ZD1839 is combined with radiation or chemotherapy in colon, head and neck, and non-small cell lung cancers. Phase I clinical trials have shown modest dose-related toxicity, and antitumor activity has been reported in a variety of malignancies including lung cancer. Future studies will certainly combine ZD1839 with chemotherapy or radiation. ZD1839 also may be effective as a chemoprevention agent because premalignant lesions often overexpress epidermal growth factor receptor.
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PMID:ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, alone and in combination with radiation and chemotherapy as a new therapeutic strategy in non-small cell lung cancer. 1189 12

Incidences of lung cancer and pleural plaque have been reported in relation to exposure to anthophyllite asbestos. To investigate the pathogenic mechanisms of anthophyllite, chemiluminescence (CL) detection of reactive oxygen metabolite (ROM) generation of human polymorphonuclear leucocytes (PMN) stimulated by anthophyllite asbestos was determined and compared with that of other asbestos and mineral fiber samples. When anthophyllite fiber sample was mixed with the luminol-primed PMN, high levels of CL which exhibited a specific time course characterized by two separate peaks were induced. The CL induced by anthophyllite sample was greater than that induced by chrysotile, crocidolite, and amosite asbestos. We further investigated the two peaks of CL using specific inhibitors of signal transduction mechanisms. The two peaks of CL by anthophyllite sample were different in sensitivity to cytochalasin B and genistein; the former relates to the cytoskeleton-dependent mechanism and the latter has been shown to inhibit tyrosine kinase, which resides in the pathway to cause PMN activation. The strong ROM reaction of PMN by anthophyllite suggests that the surface characteristics of the fiber may participate in the pathogenic mechanisms of anthophyllite asbestos.
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PMID:Chemiluminescent detection of induced reactive oxygen metabolite production of human polymorphonuclear leucocytes by anthophyllite asbestos. 1189 66

Small cell lung cancers (SCLCs), many non-SCLCs, and other cancers have neuroendocrine features, including paracrineand autocrine growth stimulation by various neuropeptides. Interference with this pathway is an attractive target for novel therapies. We developed a novel bradykinin antagonist dimer, CU201 (B9870), that acts as a "biased agonist" for neuropeptides by blocking G(alphaq) signaling and activating G(alpha12,13) signaling. CU201 induced apoptosis and complete growth inhibition in various lung cancer and other cancer cell lines. CU201 was 10-fold more potent than substance P derivatives and was stable in serum for >7 days. In this study, we evaluated the ability of CU201 to produce additive or synergistic growth inhibition in combination with various antitumor agents used in lung cancer therapy. We found that CU201 produced additive or synergistic growth inhibition when combined with doxorubicin, etoposide, cisplatin, vinorelbine, and paclitaxel for SCLC lines and with paclitaxel and ZD1839, an epidermal growth factor receptor tyrosine kinase inhibitor, for non-SCLC cell lines. Pharmacokinetic parameters associated with the i.v. administration of CU201 were evaluated in normal mice, and the effects of CU201 on the growth of human lung cancer xenografts were evaluated in athymic nude mice. In CD2F1 mice given an i.v. bolus infusion of 5 mg/kg, the c(max) was 5773 ng/ml (5 microM), and the decay was biexponential. When fitted to a two-compartment model, the t(1/2alpha) was 14.4 min, and the t(1/2beta) was 44.3 h, indicating a long terminal half-life consistent with the prolonged in vitro effects. CU201 inhibited the growth of human lung cancers in athymic nude mice by the intratumoral, s.c., and i.p. routes at a dose of 5 mg/kg/day. This dose is >10-fold less than the dose of substance P derivatives used to inhibit SCLC xenografts in nude mice. We conclude that CU201 should undergo further preclinical toxicology studies in its development as a novel targeted therapy for the treatment of lung cancers with neuroendocrine features. These studies are in progress through the NCI RAID mechanism.
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PMID:Bradykinin antagonist dimer, CU201, inhibits the growth of human lung cancer cell lines in vitro and in vivo and produces synergistic growth inhibition in combination with other antitumor agents. 1200 49


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