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)

Cyclooxygenase-2 (COX-2), the enzyme at the rate-limiting step of prostanoid production, has been found to be overexpressed in human lung cancer. To evaluate lung tumor COX-2 modulation of antitumor immunity, we studied the antitumor effect of specific genetic or pharmacological inhibition of COX-2 in a murine Lewis lung carcinoma (3LL) model. Inhibition of COX-2 led to marked lymphocytic infiltration of the tumor and reduced tumor growth. Treatment of mice with anti-PGE2 mAb replicated the growth reduction seen in tumor-bearing mice treated with COX-2 inhibitors. COX-2 inhibition was accompanied by a significant decrement in IL-10 and a concomitant restoration of IL-12 production by APCs. Because the COX-2 metabolite PGE2 is a potent inducer of IL-10, it was hypothesized that COX-2 inhibition led to antitumor responses by down-regulating production of this potent immunosuppressive cytokine. In support of this concept, transfer of IL-10 transgenic T lymphocytes that overexpress IL-10 under control of the IL-2 promoter reversed the COX-2 inhibitor-induced antitumor response. We conclude that abrogation of COX-2 expression promotes antitumor reactivity by restoring the balance of IL-10 and IL-12 in vivo.
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PMID:Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. 1060 31

Cyclooxygenase-2 (COX-2; Ptgs2) acts as a tumor promoter in rodent models for colorectal cancer, but its precise role in carcinogenesis remains unclear. We evaluated the contribution of host-derived COX-1 and COX-2 in tumor growth using both genetic and pharmacological approaches. Lewis lung carcinoma (LLC) cells grow rapidly as solid tumors when implanted in C57BL/6 mice. We found that tumor growth was markedly attenuated in COX-2(-/-), but not COX-1(-/-) or wild-type mice. Treatment of wild-type C57BL/6 mice bearing LLC tumors with a selective COX-2 inhibitor also reduced tumor growth. A decrease in vascular density was observed in tumors grown in COX-2(-/-) mice when compared with those in wild-type mice. Because COX-2 is expressed in stromal fibroblasts of human and rodent colorectal carcinomas, we evaluated COX-2(-/-) mouse fibroblasts and found a 94% reduction in their ability to produce the proangiogenic factor, VEGF. Additionally, treatment of wild-type mouse fibroblasts with a selective COX-2 inhibitor reduced VEGF production by 92%.
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PMID:Host cyclooxygenase-2 modulates carcinoma growth. 1084 6

Both simultaneous and sequential exposure to arsenite and benzo[a]pyrene (BaP) potentially occur in human populations drinking arsenic-contaminated water or burning arsenic-contaminated coal. Although arsenite and BaP are both well-documented hazardous substances and human carcinogens, interactions between these two agents have not been well defined. In this study, we demonstrated that posttreatment with arsenite synergistically enhanced the cytotoxicity of BaP for a human lung adenocarcinoma cell line, CL3. In contrast, pretreatment of CL3 cells with arsenite attenuated BaP cytotoxicity. Involvement of heat-shock protein 70 and heme oxygenase-1 in this arsenite-mediated attenuation of BaP cytotoxicity was ruled out. Our data also indicated that arsenite pretreatment did not affect the BaP-mediated induction of CYP1A1, the initial enzyme involved in its metabolic activation, but did result in a significant decrease in mRNA and protein levels of cyclooxygenase-2 (COX-2), which is required to convert the BaP metabolite BaP 7,8-dihydrodiol to the ultimate epoxide. In contrast to the high susceptibility of CL3 cells to BaP, the human lung carcinoma cells, H460, and CL3R15 cells (arsenic-resistant CL3 cells) showed normal CYP1A1 inducibility by BaP, had negligible amounts of COX-2, and were highly resistant to BaP. The involvement of COX-2 in BaP activation was confirmed by transfection of H460 cells with a recombinant adenovirus, Ad-pgk-Cox2, coding for COX-2, which resulted in a significant increase in the levels of the COX-2 product prostaglandin E2 in the medium and in the susceptibility of H460 cells to BaP. The present study confirms the importance of COX-2 in BaP activation and demonstrates that the arsenite-mediated attenuation of BaP cytotoxicity is mediated by a reduction in COX-2 levels.
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PMID:Arsenite pretreatment attenuates benzo[a]pyrene cytotoxicity in a human lung adenocarcinoma cell line by decreasing cyclooxygenase-2 levels. 1191 89

Cigarette smoke (CS) is a major cause of a variety of malignancies including cancers of the larynx, oral cavity and pharynx, esophagus, pancreas, kidney, bladder and lung. The signal transduction pathway that mediates the effects of CS is not well understood but nuclear factor-kappa B (NF-kappaB) is probably involved. The gas phase of CS contains free radicals such as superoxide radicals, hydroxyl radicals and hydrogen peroxide, which potentially can activate NF-kappaB. Benzo[a]pyrene, another potent carcinogen of CS, can also activate NF-kappaB, but by an as yet unknown mechanism. Various other agents that activate NF-kappaB are either tumor initiators or tumor promoters, and NF-kappaB activation can block apoptosis, promote proliferation and mediate tumorigenesis. Therefore, NF-kappaB is an ideal target for preventing CS-induced lung carcinogenesis. Thus, agents that abrogate NF-kappaB activation have the potential to suppress lung carcinogenesis. Because curcumin, a diferuloylmethane, is anticarcinogenic, we investigated the effect of this phytochemical on CS-induced NF-kappaB activation and NF-kappaB-regulated gene expression in human non-small cell lung carcinoma cells. Exposure of cells to CS induced persistent activation of NF-kappaB, and pre-treatment with curcumin abolished the CS-induced DNA-binding of NF-kappaB, IkappaBalpha kinase activation, IkBalpha phosphorylation and degradation, p65 nuclear translocation and CS-induced NF-kappaB-dependent reporter gene expression. The inhibition of NF-kappaB activation correlated with suppression of CS-induced NF-kappaB-dependent cyclin D1, cyclooxygenase-2 and matrix metalloproteinase-9 expression. Overall our results indicate that CS-induced NF-kappaB activation and NF-kappaB-regulated gene expression in human non-small cell lung carcinoma cells is suppressed by curcumin through suppression of IkappaBalpha kinase.
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PMID:Curcumin (diferuloylmethane) down-regulates cigarette smoke-induced NF-kappaB activation through inhibition of IkappaBalpha kinase in human lung epithelial cells: correlation with suppression of COX-2, MMP-9 and cyclin D1. 1280 25

Combined modality therapy represents current standard therapy for locoregionally advanced non-small cell lung cancer. In particular, concomitant chemoradiotherapy has emerged as the preferred approach. At the same time, efforts to increase locoregional and systemic antitumor activity are necessary to further improve long-term survival rates for these patients. In recent years, multiple cellular targets have emerged in the development of novel antitumor therapies. Several of these are of high relevance in the carcinogenesis of lung cancer including the epidermal growth factor receptor (EGFR), the ras signaling pathway, tumor angiogenesis, and cyclooxygenase-2 (COX-2) expression. Novel agents directed against these targets are currently under development with promising early results in non-small cell lung cancer when administered as single agents or in combination with chemotherapy in stage IV or recurrent disease. Similarly their use with concurrent radiation therapy is supported by preclinical models. Selected early clinical trials utilizing these agents in combination with radiotherapy or chemoradiotherapy are discussed.
Lung Cancer 2003 Aug
PMID:Targeted therapies for stage III non-small cell lung cancer: integration in the combined modality setting. 1286 70

Lung cancer is one of the most common causes of cancer-related mortality throughout the world, and the incidence continues to increase. Smoking is the number one cause of lung cancer. Emerging data have implicated cyclooxygenase-2 (COX-2) and prostanoid production in the pathogenesis of lung carcinoma. In invasive lung tumors, COX-2 upregulation has been reported in up to 90% of cases. COX-2 upregulation is an early event in the development of non-small-cell lung cancer and may be integral to the development of new blood vessels and production of specific proteases that are critical to growth and spread of lung malignancies. COX-2 inhibitors are known to enhance the chemosensitivity in COX-2 overexpressing lung cancer cell lines. Recently, we have demonstrated that selective COX-2 inhibitors also enhance the effect of radiation in COX-2 overexpressed cells. Therefore, inhibitors of COX-2 in combination with chemoradiation therapy may be an alternative strategy that can be tested in clinical trials. The combination of COX-2 inhibitors and radiation suggest a complementary strategy to target angiogenesis while potentially minimizing the impact on quality of life. Currently, several groups are conducting clinical trials in cervix cancer, lung cancer, and brain tumors, using inhibitors of COX-2 in combination with chemotherapy and radiation therapy. These clinical trials will help to elucidate the role of this interesting class.
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PMID:COX-2 inhibitor as a radiation enhancer: new strategies for the treatment of lung cancer. 1290 60

Cyclooxygenase-2 (COX-2) is an enzyme involved in prostaglandin production in pathologic states such as inflammatory processes and cancer. The enzyme is often overexpressed in premalignant lesions and cancer, including cancers of the lung and esophagus. Inhibition of this enzyme with selective COX-2 inhibitors was found to enhance tumor response to radiation in preclinical studies, suggesting that these agents can improve the response of various cancers to radiotherapy. On the basis of these preclinical findings, clinical trials of the combination of celecoxib, a selective COX-2 inhibitor, with radiotherapy were initiated in patients with lung carcinoma and with chemoradiotherapy in patients with esophageal carcinoma. The rationale for using selective COX-2 inhibitors is discussed, and the current clinical protocols and the initial findings are described.
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PMID:Combination of a COX-2 inhibitor with radiotherapy or radiochemotherapy in the treatment of thoracic cancer. 1290 63

Cyclooxygenase-2 (COX-2) is an enzyme involved in prostaglandin production in pathologic states such as inflammatory disorders and cancer. The enzyme is often overexpressed in premalignant lesions and cancer of the lung. Overexpression of COX-2 in lung cancer is associated with more aggressive biological tumor behavior and adverse patient outcome. In preclinical studies, inhibition of this enzyme with selective COX-2 inhibitors enhances tumor response to radiation and chemotherapeutic agents. These findings have been rapidly advanced to clinical oncology. Clinical trials of the combination of selective COX-2 inhibitors with radiation therapy, chemotherapy, or both in patients with lung cancer have been initiated and some preliminary results are available. In this review, we describe the relationship between overexpression of COX-2 and lung cancer, the antitumor effect of selective COX-2 inhibitors, discuss the rationale for using selective COX-2 inhibitors combined with radiation therapy and chemotherapy, and summarize current clinical protocols and initial findings.
Clin Lung Cancer 2003 May
PMID:Role of cyclooxygenase-2 inhibitors in combination with radiation therapy in lung cancer. 1459 1

Irinotecan possesses significant single-agent activity in non-small-cell lung cancer (NSCLC) and is active in combination with either cisplatin or carboplatin. Two phase III trials completed in Japan have suggested that the combination of irinotecan/cisplatin yields superior survival rates in stage IV NSCLC patients compared to vindesine/cisplatin. The principal toxicities of the irinotecan/cisplatin regimen are neutropenia and diarrhea. This regimen is currently being tested in Japan against regimens commonly used in the United States, such as cisplatin/gemcitabine, cisplatin/vinorelbine, and carboplatin/paclitaxel. These studies include evaluation of monthly as well as weekly schedules of cisplatin in combination with irinotecan as well as a triplet regimen of irinotecan/carboplatin/paclitaxel. Ongoing trials are evaluating these regimens as well as irinotecan/carboplatin and several nonplatinum-based irinotecan-containing doublets in both the first- and second-line treatment of advanced NSCLC. Several ongoing trials are attempting to integrate irinotecan with thoracic radiation therapy in stage III NSCLC. These trials are using irinotecan-containing regimens as induction and concurrent therapy with thoracic radiation therapy. Irinotecan is also being evaluated in the preoperative setting in early-stage resectable NSCLC. Many of these trials are also incorporating celecoxib, a potent inhibitor of the cyclooxygenase-2 pathway, in combination with irinotecan-containing regimens in both advanced as well as early-stage NSCLC. Future trials should focus on the integration of the new targeted agents in combination with irinotecan-containing regimens in all stages of NSCLC.
Clin Lung Cancer 2002 Nov
PMID:Irinotecan in non-small-cell lung cancer: status of ongoing trials. 1465 36

Recent advances in the understanding of the biology and molecular biology of lung cancer has provided targets for novel therapeutic and chemoprevention strategies. The eicosanoid/prostaglandin signal pathway is involved in the metabolism of membrane phospholipids to end products that are involved in apoptosis, proliferation, differentiation, and angiogenesis. Abnormalities in this pathway occur frequently in lung cancer, including the overexpression of cytoplasmic phospholipase A2, cyclooxygenase-2 (COX-2), prostaglandin E (PGE) synthase, PGE2, 5-lipoxygenase (LOX), 8-LOX, and 12-LOX. Increased levels of PGE2, 5-LOX, 8-LOX, and 12-LOX promote tumor proliferation and angiogenesis and inhibit apoptosis. On the other hand, levels of proapoptotic, antiangiogenic, and antiproliferative products are frequently decreased in lung cancer due to decreased levels of enzymes such as prostacyclin synthase. These abnormalities provide a rationale for the use of inhibitors of overexpressed enzymes or replacement of anticarcinogenic end products, and such agents have been studied in preclinical and clinical trials.
Clin Lung Cancer 2002 May
PMID:The future of cyclooxygenase-2 inhibitors and other inhibitors of the eicosanoid signal pathway in the prevention and therapy of lung cancer. 1466 36


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