Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocyte growth factor (HGF)/scatter factor (SF) is a multifunctional factor that stimulates epithelial cell motility, invasion and morphogenesis. Its receptor is a transmembrane tyrosine kinase encoded by the Met proto-oncogene. Several studies have suggested a possible role for HGF/Met in tumor development and progression. To investigate the potential roles of Met in human lung cancer biology, we have studied the mRNA and protein expression of Met in normal lung tissue, primary non-small cell lung carcinoma (NSCLC), and NSCLC cell lines. The results indicated a differential pattern of Met expression among various subtypes of NSCLC. The majority of squamous cell carcinoma (SQCC), either in vivo or in vitro, expressed Met mRNA and its protein product at levels much lower than or similar to normal lung tissue or bronchial epithelium. Moreover, SQCC characteristically over-expressed a variant Met mRNA which corresponds to a 5' partially deleted transcript produced by alternative splicing. In contrast, the expression of Met mRNA and its protein product in adenocarcinoma (ADC) and large cell undifferentiated carcinoma were more heterogeneous. Overexpression was demonstrated in approximately 35% and 20% of these subtypes of NSCLC, respectively. Among ADC, intermediate to high levels of Met immunoreactivity correlated with greater degree of tumor differentiation. Furthermore, an accentuation of Met immunoreactivity was often noted in cancer cells at the advancing edge of tumors. These findings support a role for Met in lung cancer cell invasion and differentiation in vivo, but its expression and functions may be modified by the differentiation phenotype of the tumor cells.
Lung Cancer 1998 Apr
PMID:Differential expression of Met/hepatocyte growth factor receptor in subtypes of non-small cell lung cancers. 969 82

The epidermal growth factor receptor (EGFR) is thought to mediate the action of the mitogens EGF and tumour growth factor-alpha (TGF-alpha) in a variety of cancers, including those of the lung, breast and ovary. A number of new selective inhibitors of EGFR tyrosine kinase have now been developed as potential new antitumour agents. We used a potent inhibitor of this tyrosine kinase, 6-amino-4-[(3-bromophenyl)amino]-7-(methylamino)quinazoline (SN 25531; PD 156273), to determine the responses of primary cultures derived from patients with cancer of the lung, ovary, breast, cervix and endometrium. Cells were cultured in 96-well plates and proliferation assessed by incorporation of 3H-thymidine. Measured growth inhibitory concentrations IC50 values) varied from 1 nM to 14 microM with a 1000-fold differential between sensitive and resistant cultures. Results were compared with rates of proliferation, estimated using a paclitaxel-based method. We also measured the IC50 values for the tyrosine kinase inhibitor using a number of established human cell lines, and compared them with EGFR content using fluorescent antibody staining and flow cytometry. The presence of EGFR was found to be necessary, but not sufficient, for in vitro response. Only a small number of cell lines (3 of 7 for lung, 1 of 7 for ovarian, 2 of 3 squamous cell and 0 of 12 for melanoma) were sensitive to the tyrosine kinase inhibitor. In contrast, 40 of the 50 primary cultures (including 14 of 15 lung cancer samples and 14 of 19 ovarian cancer samples) were sensitive.
 ...
PMID:Inhibition of growth of primary human tumour cell cultures by a 4-anilinoquinazoline inhibitor of the epidermal growth factor receptor family of tyrosine kinases. 984 59

Several studies have suggested that biochemical or molecular markers examined in non-small cell lung cancer carry prognostic or treatment response information. Non-small cell lung cancer patients whose tumors have neuroendocrine (NE) features may be more responsive to chemotherapy. In addition, increased expression of HER2 (c-erbB-2), a membrane-bound receptor with tyrosine kinase activity, has been associated with shortened survival. The Cancer and Leukemia Group B (CALGB) performed a study of patients with stage IIIA (N2 nodes positive) non-small cell lung cancer in which patients received initial chemotherapy followed by surgery, then post-operative therapy consisting of sequential chemotherapy and radiation therapy. Since all patients underwent mediastinoscopy, this provided an opportunity to compare pre- and post-chemotherapy tumor specimens to test the hypothesis that these proteins would predict treatment response. In particular, we hypothesized that the post-chemotherapy specimens would be enriched for NE marker negative cells because of the increased sensitivity of NE positive cells to chemotherapy. We performed immunohistochemical analysis for a panel of NE markers [neuron-specific enolase (NSE), Leu-7, chromogranin A (ChrA), synaptophysin (Syn)], HER2 and CEA to determine if there was an effect of therapy on the percentage of cells expressing these markers. Secondary endpoints were a correlation with chemotherapy response and survival. Slides were scored for intensity (0-4) and percentage of cells positive (0-4). Of 61 eligible patients, there were 38 with both pre- and post-chemotherapy specimens. When both intensity of staining and percentage of positive cells were considered, post-chemotherapy specimens had a higher percentage of positive NE markers compared with pre-chemotherapy. In addition, there was no correlation between NE marker, HER2 or CEA expression (prior to or post treatment) and response to chemotherapy or survival. These data do not support the hypothesis that NE positive tumor cells are preferentially killed by chemotherapy in patients with stage IIIA non-small cell lung cancer.
Lung Cancer 1998 Sep
PMID:Analysis of neuroendocrine markers, HER2 and CEA before and after chemotherapy in patients with stage IIIA non-small cell lung cancer: a Cancer and Leukemia Group B study. 985 98

We established a drug sensitivity panel consisting of 24 human lung cancer cell lines. Using this panel, we evaluated 26 anti-cancer agents: three alkylators, three platinum compounds, four antimetabolites, one topoisomerase I inhibitor, five topoisomerase II inhibitors, seven antimitotic agents and three tyrosine kinase inhibitors. This panel showed the following: a) Drug sensitivity patterns reflected their clinically-established patterns of action. For example, doxorubicin and etoposide were shown to be active against small cell lung cancer cell lines and mitomycin-C and 5-fluorouracil were active against non-small cell lung cancer cell lines, in agreement with clinical data. b) Correlation analysis of the mean graphs derived from the logarithm of IC50 values of the drugs gave insight into the mechanism of each drug's action. Thus, two drug combinations with reverse or no correlation, such as the combination of cisplatin and vinorelbine, might be good candidates for the ideal two drug combination in the treatment of lung cancer, as is being confirmed in clinical trials. c) Using cluster analysis of the cell lines in the panel with their drug sensitivity patterns, we could classify the cell lines into four groups depending on the drug sensitivity similarity. This classification will be useful to elucidate the cellular mechanism of action and drug resistance. Thus, our drug sensitivity panel will be helpful to explore new drugs or to develop a new combination of anti-cancer agents for the treatment of lung cancer.
 ...
PMID:Establishment of a drug sensitivity panel using human lung cancer cell lines. 1035 21

Interest in the role of the insulin-like growth factor (IGF) axis in growth control and carcinogenesis has recently been increased by the finding of elevated serum insulin-like growth factor I (IGF-I) levels in association with three of the most prevalent cancers in the United States: prostate cancer, colorectal cancer, and lung cancer. IGFs serve as endocrine, autocrine, and paracrine stimulators of mitogenesis, survival, and cellular transformation. These actions are mediated through the type 1 IGF-receptor (IGF-1R), a tyrosine kinase that resembles the insulin receptor. The availability of free IGF for interaction with the IGF-1R is modulated by the insulin-like growth factor-binding proteins (IGFBPs). IGFBPs, especially IGFBP-3, also have IGF-independent effects on cell growth. IGF-independent growth inhibition by IGFBP-3 is believed to occur through IGFBP-3-specific cell surface association proteins or receptors and involves nuclear translocation. IGFBP-3-mediated apoptosis is controlled by numerous cell cycle regulators in both normal and disease processes. IGFBP activity is also regulated by IGFBP proteases, which affect the relative affinities of IGFBPs, IGFs and IGF-1R. Perturbations in each level of the IGF axis have been implicated in cancer formation and progression in various cell types.
 ...
PMID:Role of insulin-like growth factors and their binding proteins in growth control and carcinogenesis. 1069 60

Malignant pleural effusion (PE) is associated with advanced human lung cancer. We found recently, using a nude mouse model, that vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is responsible for PE induced by non-small cell human lung carcinoma cells. The purpose of this study was to determine the therapeutic potential of a VEGF/VPF receptor tyrosine kinase phosphorylation inhibitor, PTK 787, against PE formed by human lung adenocarcinoma (PC14PE6) cells. PTK 787 did not affect the in vitro proliferation of PC14PE6 cells, whereas it specifically inhibited proliferation of human dermal microvascular endothelial cells stimulated by VEGF/VPF. A specific platelet-derived growth factor receptor tyrosine kinase inhibitor, CGP57148 (used as a control because PTK 787 also inhibits platelet-derived growth factor receptor tyrosine kinases), had no effect on proliferation of PC14PE6 or human dermal microvascular endothelial cells. i.v. injection of PC14PE6 cells into nude mice produced lung lesions and a large volume of PE containing a high level of VEGF/VPF. Oral treatment with CGP57148 had no effect on PE or lung metastasis. In contrast, oral treatment with PTK 787 significantly reduced the formation of PE but not the number of lung lesions. Furthermore, treatment with PTK 787 significantly suppressed vascular hyperpermeability of PE-bearing mice but did not affect the VEGF/VPF level in PE or expression of VEGF/VPF protein and mRNA in the lung tumors of PC14PE6 cells in vivo. These findings indicate that PTK 787 reduced PE formation mainly by inhibiting vascular permeability, suggesting that this VEGF/VPF receptor tyrosine kinase inhibitor could be useful for the control of malignant PE.
 ...
PMID:Treatment for malignant pleural effusion of human lung adenocarcinoma by inhibition of vascular endothelial growth factor receptor tyrosine kinase phosphorylation. 1074 21

Irinotecan(CPT-11), Taxol, Taxotere, vinorelbine and gemcitabine have shown a significant activity in previously untreated non-small cell lung cancer (NSCLC). Cisplatin(CDDP) combined with vinorelbine, gemcitabine or tirapazamine was significantly superior in survival to CDDP alone in the treatment of advanced NSCLC. Patients with NSCLC treated with combination of CDDP and Taxol or vinorelbine lived longer than those treated with conventional CDDP-based chemotherapy. CPT-11, topotecan, taxol and amrubicin have demonstrated to be active against small cell lung cancer(SCLC). Combination of CPT-11 and CDDP have had a higher response rate, and better median survival(13 months) in patients with extensive disease SCLC. Clinical trials of target-based drugs including matrix metalloprotenase inhibitors, anti-angiogenesis, tyrosine kinase inhibitors, farnesyl transferase inhibitors and monoclonal antibodies have been initiated in solid tumors including lung cancer. Development of new anti-cancer agents is essential to improve outcomes of patients with lung cancer.
 ...
PMID:[Current perspectives of new agents in lung cancer]. 1082 57

The interaction between the erbB tyrosine kinase receptors and their ligands plays an important role in tumor growth via the regulation of autocrine and paracrine loops. We report the effect of heregulin beta1, the ligand for erbB-3 and erbB-4 receptors, on the regulation of vascular endothelial growth factor (VEGF) expression, using a panel of breast and lung cancer cell lines with constitutive erbB-2 overexpression or engineered to stably overexpress the erbB-2 receptor. We demonstrate that heregulin beta1 induces VEGF secretion in most cancer cell lines, while no significant effect was observed in normal human mammary and bronchial primary cells. Overexpression of erbB-2 receptor results in induction of the basal level of VEGF and exposure to heregulin further enhances VEGF secretion. This is associated with increased VEGF mRNA expression. In contrast, VEGF induction is significantly decreased in a T47D cell line where erbB-2 is functionally inactivated. Conditioned media from heregulin-treated cancer cells, but not from normal cells, stimulates endothelial cell proliferation; this paracrine stimulation is inhibited by co-exposure to a specific VEGF neutralizing antibody. Furthermore, heregulin-mediated angiogenesis is observed in the in vivo CAM assay. This study reports the first evidence of VEGF regulation by heregulin in cancer cells. Oncogene (2000) 19, 3460 - 3469
 ...
PMID:Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis. 1091 4

Increased expression of cyclooxygenase-2 (COX-2) expression has been observed in several human tumor types and in selected animal and cell culture models of carcinogenesis, including lung cancer. Increased expression of COX-2 and production of prostaglandins appear to provide a survival advantage to transformed cells through the inhibition of apoptosis, increased attachment to extracellular matrix, increased invasiveness, and the stimulation of angiogenesis. In the present studies, we found that transforming growth factor beta1 (TGF-beta1) and epidermal growth factor (EGF) synergistically induced the expression of COX-2 and prostaglandin E2 (PGE2) production in mink lung epithelial (Mv1Lu) cells. EGF, but not PDGF or IGF-1, was able to inhibit TGF-beta1-induced apoptosis in Mv1Lu cells and this effect was blocked by NS-398, a selective inhibitor of COX-2 activity, suggesting a possible role for COX-2 in the anti-apoptotic effect of EGF receptor ligands. The combination of TGF-beta1 and EGF also significantly induced COX-2 expression in rat intestinal epithelial (RIE-1) cells and completely prevented sodium butyrate (NaBu)-induced apoptosis. The synergistic induction of COX-2 by TGF-beta1 and EGF was not observed in R1B-L17 cells, a line derived from Mv1Lu cells that lacks the TGF-beta type-I receptor. AG1478, a selective inhibitor of EGF receptor tyrosine kinase activity, completely suppressed the induction of COX-2 expression by either EGF or TGF-beta1+EGF. Also, PD98059, a specific inhibitor of MEK/ERK pathway, and SB203580, a specific inhibitor of p38 MAPK activity, significantly inhibited the induction of COX-2 in response to combined EGF and TGF-beta1. These results suggest an important collaborative interaction of TGF-beta1 and EGF signaling in the induction of COX-2 and prostaglandin production in Mv1Lu cells.
 ...
PMID:Synergistic induction of cyclooxygenase-2 by transforming growth factor-beta1 and epidermal growth factor inhibits apoptosis in epithelial cells. 1093 98

Have we made any progress in the treatment of advanced non-small cell lung cancer (NSCLC) over the past 15 years? After hearing the Eastern Cooperative Oncology Group (ECOG) 1594 presented by Dr. Joan Schiller at the plenary session of the 36th Annual Meeting of ASCO, it is hard to be certain. SCHILLER: reported the results of one of the world's largest randomized trials in metastatic lung cancer comparing four platinum-based doublets. There were no differences in survival (primary endpoint) or response between these four regimens, although the cisplatin/gemcitabine arm had a superior time to progression. In her commentary on this study, Dr. Francis Shepherd concluded that progress in the treatment of metastatic lung cancer has occurred at "a snail's pace." Despite the disappointing results of ECOG 1594, there were notable trials describing new agents with novel mechanisms of action reported at this year's ASCO meeting. In small-cell lung cancer, the combination of cisplatin/ irinotecan was found to be superior to cisplatin/etoposide. For NSCLC, novel agents Iressa anti-epidermal growth factor receptor tyrosine kinase and anti-vascular endothelial growth factor monoclonal antibody appear promising.
 ...
PMID:Lung cancer highlights. 1096 93


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>