Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001418 (adenocarcinoma)
 68,496 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over-expression of aldose reductase (AR) has been observed in many cancer cells. To clarify the role of AR in tumor cells, we investigated the pathways mediating expression of the AR gene induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent tumor promoter. In A549 human lung adenocarcinoma cells, TPA elicited a dose- and time-dependent increase in AR mRNA level with an elevated enzyme activity. The TPA-induced increase in mRNA level and promoter activity of the AR gene was significantly attenuated in the presence of an inhibitor of protein kinase C, tyrosine kinase, or nuclear factor kappaB (NF-kappaB). TPA augmented the NF-kappaB-dependent gene transcription, indicating the involvement of NF-kappaB in this regulation. Accumulation of TPA-treated cells in S phase was almost completely abolished in the presence of ethyl 1-benzyl-3-hydroxy-2(5H)-oxopyrrole-4-carboxylate, an AR inhibitor. Taken together, TPA augmented the promoter activity of the AR gene via the activation of protein kinase and NF-kappaB. The inhibition of AR may assist in the chemotherapy of malignant tumors by suppressing the rapid growth of cancer cells.
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PMID:Phorbol ester up-regulates aldose reductase expression in A549 cells: a potential role for aldose reductase in cell cycle modulation. 1592 7

Pulmonary adenocarcinoma (PAC) is the most common type of human lung cancer. A diagnosis of PAC, history of non-smoking and presence of mutations in the EGFR are predictive factors for responsiveness of lung cancer to EGFR-specific tyrosine kinase inhibitors. Unfortunately, less than 50% of PAC cases demonstrate this mutation-based responsiveness. Our immunohistochemical analysis of NNK-induced PAC in hamsters demonstrates the simultaneous over-expression of a beta2-adrenergic receptor pathway, including PKA, cAMP, CREB and phosphorylated CREB and of an EGFR pathway, including over-expression of EGFR-specific phosphorylated tyrosine kinase, Raf-1 and ERK1/2 and their phosphorylated forms. These findings implicate, for the first time, PKA/CREB-mediated signaling in the development and regulation of any type of lung cancer. In light of reports that NNK acts as a beta-adrenergic agonist and that beta-blockers inhibit the growth of PAC of Clara cell lineage in the NNK hamster model and in human cancer cell lines from smokers, our current data suggest transactivation of the EGFR pathway via beta-adrenergic signaling as a novel regulatory mechanism in a subpopulation of PACs in smokers. Taken together, these data point to PKA/CREB as novel targets for the development of cancer therapeutics for PAC patients non-responsive to EGFR-specific tyrosine kinase inhibitors.
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PMID:NNK-induced hamster lung adenocarcinomas over-express beta2-adrenergic and EGFR signaling pathways. 1594 88

Gefitinib (Iressa), an orally-active tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), is the first approved molecular-targeted drug for the management of patients with advanced non-small cell lung cancer (NSCLC). Two Phase II trials (IDEAL [Iressa Dose Evaluation in Advanced Lung Cancer]-1 and -2), evaluated the efficacy of gefitinib in advanced NSCLC patients who received < or = 2 (IDEAL1) or > or = 2 (IDEAL2) previous chemotherapy regimens. The response rate and disease control rate in IDEAL1 and -2 was 18/12% and 54/42%, respectively. The median survival time and one-year survival rate in both studies were approximately 7 months and 30%, respectively. As gefitinib has demonstrated antitumour activity and an acceptable tolerability profile not typically associated with cytotoxic adverse events, such as hematological toxicities, combinations with cytotoxic drugs have been evaluated. Disappointingly, in chemotherapy-naive patients with advanced NSCLC, gefitinib 250 and 500 mg/day combined with platinum-based chemotherapy (gemcitabine/cisplatin or paclitaxel/carboplatin) did not produce prolonged survival, compared with chemotherapy alone in two large, randomised, placebo-controlled, multi-centre Phase III trials (INTACT [Iressa NSCLC Trial Assessing Combination Treatment]-1 and -2). Furthermore, in a recent randomised, placebo-controlled, Phase III trial (ISEL: IRESSA Survival Evaluation in Lung cancer), gefitinib failed to prolong survival compared with placebo in patients with advanced NSCLC who had failed one or more lines of chemotherapy. Subgroup analysis of ISEL suggested improved survival in patients of Asian origin and non-smokers. In addition, subset analyses of IDEAL and several retrospective studies have indicated that female gender, adenocarcinoma histology (especially bronchial alveolar carcinoma), non-smoker status and Asian ethnicity are factors which predict to response to gefitinib. Two types of somatic mutation clustered around the ATP binding pocket in the tyrosine kinase domain of the EGFR gene have been reported as possible surrogate biological markers for predicting response to gefitinib. Appropriate patient selection by clinical characteristics or genetical information is needed, both for future clinical trials of gefitinib and its routine use in the clinic among patients with advanced NSCLC.
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PMID:Gefitinib in non-small cell lung cancer. 1595 26

Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is an active agent in non-small cell lung cancer, and rapidly relieves bronchorrhea in patients with bronchioloalveolar carcinoma before the improvement of radiological findings. In addition, epidermal growth factor regulates mucin secretion in normal airway goblet cells. The present study was designed to clarify whether gefitinib modifies mucin production in lung cancer cell lines apart from its anti-proliferative effects, using A549 adenocarcinoma and NCI-H292 mucoepidermoid carcinoma cells expressing EGFR and MUC5AC mRNA. Mucin synthesis was measured by RT-PCR and ELISA, and MAPK and Akt, the downstream targets of EGFR, were examined by Western blotting assay. The clinically-achievable concentration of 1muM gefitinib inhibited the growth of both cells by only 10%, but gefitinib suppressed MUC5AC mRNA levels subsequent to a decrease in intracellular and secreted MUC5AC protein. Gefitinib also inhibited the phosphorylation of MAPK and Akt, and the selective inhibitors PD98059 and LY294002 also suppressed MUC5AC protein synthesis. These findings suggest that gefitinib may inhibits MUC5AC synthesis, at least in part, through MAPK and Akt signaling pathways. Thus, gefitinib inhibits mucin production, which is encouraging for trials involving its use against bronchorrhea in patients with lung cancer.
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PMID:Gefitinib inhibits MUC5AC synthesis in mucin-secreting non-small cell lung cancer cells. 1600 52

Epidermal growth factor receptor 1 (EGFR 1 ) is a 170-kd glycoprotein that plays many roles in the growth of non-small cell lung cancer (NSCLC). There are four known receptors in the EGFR family. Binding of a ligand such as epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha) causes EGFR to undergo a conformational change leading to autophosphorylation of EGFR and activation of the EGFR growth factor pathway. The protein products of the genes that are then expressed increase cell proliferation and angiogenesis and inhibit programmed cell death. EGFR is expressed in 40% to 80% of NSCLC. EGFR tyrosine kinase activity can be inhibited by antibody therapy, such as cetuximab, against the extracellular domain of EGFR or small-molecule therapy, such as gefitinib or erlotinib that blocks the adenosine triphosphate (ATP) binding site of the cytoplasmic domain. Both forms of EGFR inhibition have single-agent antitumor activity against previously treated NSCLC. Interestingly, EGFR expression does not correlate with response to EGFR inhibition therapy. Increased likelihood of responding to small-molecule therapy is associated with female gender, never smoking, adenocarcinoma, and acquired mutations of the EGFR ATP binding site in tumor cells. In previously treated NSCLC, the small-molecule erlotinib improved both quality of life and median survival as a single agent compared with best supportive care. Southwest Oncology Group 0023 is a large, phase III, randomized trial comparing concurrent chemoradiotherapy and consolidation docetaxel with or without maintenance small-molecule therapy with gefitinib. There is also strong preclinical evidence that EGFR inhibition is additive or synergistic with radiotherapy in NSCLC. In locally advanced head and neck cancer, the addition of cetuximab antibody therapy to radiation increased median survival from 28 to 54 months. Cancer and Leukemia Group B 30106 and a multi-institutional Australian phase I trial have shown that gefitinib can be added to concurrent chemoradiotherapy for stage III NSCLC without excessive toxicity. A phase I trial at the University of Chicago (Chicago, IL) has evaluated erlotinib with concurrent chemoradiotherapy in stage III NSCLC. Radiation Therapy Oncology Group 0324 is an on-going phase II trial studying cetuximab and concurrent chemoradiotherapy in stage III NSCLC.
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PMID:Inhibition of the epidermal growth factor receptor in combined modality treatment for locally advanced non-small cell lung cancer. 1601 34

Over the past few years, two epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) and erlotinib (Tarceva), have been developed for the treatment of patients with cancer. In patients with non-small cell lung cancer (NSCLC), these therapies occasionally demonstrate remarkable and durable activity. However, EGFR TKIs are active in only a small subset of patients. Responders are more often nonsmokers, of East Asian descent, and female, and have tumors with adenocarcinoma histology. In April 2004, two groups reported that a cluster of somatic mutations in the kinase domain of the EGFR are observed in the majority of NSCLCs that demonstrate remarkable responses to EGFR TKIs. These findings have been validated by other investigators and have revolutionized the manner in which clinicians are thinking about their utilization for the treatment of NSCLC. This review focuses on the clinical experience with EGFR TKIs, the present knowledge regarding the biology of EGFR mutations, the limitations of using EGFR mutational status to predict who will respond to EGFR TKIs, and the implications of this information on the use of these agents for the treatment of advanced NSCLC.
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PMID:Factors predicting response to EGFR tyrosine kinase inhibitors. 1605 33

Bronchioloalveolar carcinoma (BAC) is an important subtype of pulmonary adenocarcinoma. It has received increasing attention in recent years, due to its increasing incidence and its rate of sensitivity to epidermal growth factor-tyrosine kinase inhibitors (EGFR-TKIs). This article reviews the epidemiology, risk factors, pathology, clinical presentation, and treatment of this disease. Special focus is paid to the emerging role of oral EGFR-TKIs in Bronchioloalveolar cell carcinoma.
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PMID:Bronchioloalveolar carcinoma: a review of the epidemiology, pathology, and treatment. 1605 36

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in numerous transformed cell lines but not in most normal cells. Although this selectivity offers a potential therapeutic application in cancer, not all cancers are sensitive to TRAIL-mediated apoptosis. In this study, we observed that amiloride, a current clinically used diuretic drug, which had little or no cytotoxicity, sensitized TRAIL-resistant human prostate adenocarcinoma LNCaP and human ovarian adenocarcinoma SK-OV-3 cells. The TRAIL-mediated activation of caspase, and PARP cleavage, were promoted in the presence of amiloride. Western blot analysis showed that combined treatment with TRAIL and amiloride did not change the levels of TRAIL receptors (DR4, DR5, and DcR2) and anti-apoptotic proteins (FLIP, IAP, and Bcl-2). However, amiloride dephosphorylated HER-2/neu tyrosine kinase as well as Akt, an anti-apoptotic protein. Interestingly, amiloride also dephosphorylated PI3K and PDK-1 kinases along with PP1alpha phosphatase. In vitro kinase assay revealed that amiloride inhibited phosphorylation of kinase as well as phosphatase by competing with ATP. Taken together, the present studies suggest that amiloride enhances TRAIL-induced cytotoxicity by inhibiting phosphorylation of the HER-2/neu-PI3K-Akt pathway-associated kinases and phosphatase.
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PMID:Role of HER-2/neu signaling in sensitivity to tumor necrosis factor-related apoptosis-inducing ligand: enhancement of TRAIL-mediated apoptosis by amiloride. 1605 13

Gefitinib inhibits the ATP-binding site of the tyrosine kinase associated with the epidermal growth factor receptor. It is conceivable that gefitinib may inhibit functions of ATP-binding cassette (ABC) transporters by binding at their ATP-binding sites. The aim of this study is to systematically explore the combined effect of gefitinib and chemotherapeutic agents in gefitinib-insensitive multidrug resistant (MDR) cells that overexpress ABC transporters. MCF7 breast carcinoma cells and CL1 lung adenocarcinoma cells were both insensitive to gefitinib. MDR cancer cells were developed by stepwise escalating concentrations of each chemotherapeutic agent in culture media. Cells that overexpress P-glycoprotein (MCF7/Adr and CL1/Pac), breast cancer-resistant protein (MCF7/TPT and CL1/Tpt), and MDR-associated protein 1 (MCF7/Vp) were used in this study. All resistant mutants were insensitive to gefitinib. Gefitinib (0.3-3 micromol/L) added to culture media had no effect on IC50 values of paclitaxel, topotecan, doxorubicin, or etoposide in wild-type MCF7 or CL1 cells. In contrast, these concentrations of gefitinib caused a dose-dependent reversal of resistance to paclitaxel in CL1/Pac cells, to doxorubicin in MCF7/ADR cells, and to topotecan in CL1/Tpt and MCF7/TPT cells. Gefitinib had no influence on sensitivity to etoposide in MDR-associated protein1 overexpressing MCF7/VP cells. Topotecan efflux was inhibited and accumulation was partially restored in CL1/Tpt and MCF7/TPT cells when cells were incubated simultaneously with gefitinib. Our results suggest that the interaction of gefitinib and chemotherapeutic agents does occur in cells expressing one of these two proteins.
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PMID:Gefitinib reverses chemotherapy resistance in gefitinib-insensitive multidrug resistant cancer cells expressing ATP-binding cassette family protein. 1606 79

Hypertrophic osteoarthropathy is an important manifestation of lung carcinoma, particularly in a non-small cell tumor, and hampers quality of life. Although removal of the primary tumor usually resolves this syndrome, effective treatment in patients with advanced lung carcinoma has not been established. Recently, an orally active, selective epidermal growth factor receptor tyrosine kinase (EGFR) inhibitor ("Gefitinib") provided clinical anti-tumor activity. We describe a 71-year-old male smoker with cough, who presented with clubbed fingers. A transbronchial lung biopsy (stage T2N3M1-IV) on a cavity lesion in the left lower lobe showed the features of adenocarcinoma, while bone scintigram revealed bilaterally symmetrical abnormal uptakes in the lower extremities, suggesting secondary hypertrophic osteoarthropathy. The serum level of growth hormone was increased to 1.42 ng/ml. Chemotherapy (cisplatin, vinorelbine) was not effective. Gefitinib, as a second-line therapy, induced disappearance of the abnormal accumulation on bone scintigraphy and decrease of the cavity in the lung and of serum growth hormone. The presented case suggests that the EGFR inhibitor might be a promising option for the treatment of hypertrophic osteoarthropathy with advanced lung adenocarcinoma.
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PMID:Successful treatment of hypertrophic osteoarthropathy by gefitinib in a case with lung adenocarcinoma. 1608 Apr 71


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