ADJACENT NORMAL LUNG TISSUE SPECIMENS - CYCLOOXYGENASE-2 AND PROSTAGLANDIN E2

Cyclooxygenase (COX) enzymes are limited in prostanoid synthesis. Convert arachidonic acid to prostaglandin H2 substrate for specific prostaglandin Synthetase. COX wider - the two isoforms of COX that is expressed and inducible 1 COX - 2, are isolated, have been characterized. Many studies have now COX in human NSCLC - 2 expression showed a high component. Commercial The first exposure of non-small cell lung cancer, Huang et al, COX to - to evaluate the expression of two And adjacent normal lung tissue specimens resected non-small cell lung cancer by immunohistochemistry (33). All 15 tumor samples were evaluated displayed cytoplasmic In cancer cells, COX - 2 staining. And adjacent normal lung were observed in contrast to In alveolar epithelial COX - 2 staining, often prove positive
Cytoplasmic staining of alveolar macrophages and occasional bronchiolar The epithelium. In other studies, since confirmed these initial findings have been extended Furthermore, recent, COX in lung cancer - the importance of the two document (113) evaluated. Increasing evidence, COX tumor - shows that there are two inhibitory activity Multifaceted role in the distribution of malignant and metastatic phenotype of lung cancer Of cancer. Many genetic changes, it is necessary for the onset of lung cancer COX - 2 is expected to be a central component of this process orchestration. Of Thus, COX - 2 resistance to apoptosis (114-116) are involved in Increase in angiogenesis (117, 118) (30,119,120) to reduce the host immune
Increased invasion and metastasis (121, 122). These newly discovered molecules Mechanism of the onset of lung cancer offers new opportunities for Targeted therapy. COX - 2 is one of the goals of the study of both lungs. Chemoprevention of cancer and its treatment (92,113,123). Prostaglandin E2 (PGE2) is, COX in the lung - two metabolites present
Immune regulation (93), epithelial cell proliferation and invasion (124), micro-environment that is both autocrine and paracrine mediator of epithelial survival and (116). PGE 2 is, G four - has multiple effects through a receptor protein (GPCR). COX - block PGE 2 production or activity of the target 2-dependent Signaling, in May, the European Parliament as a receptor, COX - 2 downstream pathways COX - more serious consequences than a single tumor 2 inhibition. Many of The most recent approach to the treatment and chemoprevention of lung cancer Based on this rationale. There is also an established role for GPCR in
Epidermal growth factor receptor (EGFR) pathway transformer, which May result in increased cancer cell proliferation and migration. Krysan and colleagues were EGFR-independent activation of PGE2 in the first over of evidence Pathway MAPK / ERK, COX - suggesting that overexpression contributes to two EGFR inhibitor resistance in non-small cell lung cancer (124). These findings, the logical Pharmacological inhibition of prostaglandin E2 in combination with the EGFR Inhibitor treatment of non-small cell lung cancer. COX in cancer cells of non-small cell lung cancer prognosis - one of the first report linking the expression of two These are Khuri, COX in non-small cell lung cancer stage I - 160 sheets 2 expression to evaluate and by in situ hybridization, COX - showed that overexpression of two visible Early disease (125) in patients with shorter survival. Power COX - 2 expression is reduced, and overall survival (P = 0001) were related to both And (P = 0022) decreased disease-free survival. Furthermore, the correlation COX - 2 overexpression and poor prognosis, was independent of stage at this point Surgical removal of the patient population of NSCLC. Tsubochi and colleagues described COX-stage - I like the relationship between the 2 expression and poor prognosis Adenocarcinoma (126). These reports, along with other studies documenting Precancerous lesions increased COX - 2 expression (127,128), a common polymorphism Increased risk of lung cancer (129) COX is associated with the - with 2 inhibitor gene, and Epidemiological studies show a decrease in the incidence of lung cancer
Patients who take aspirin regularly (130), COX in support of all - the involvement of two
Pathogenesis of lung cancer. High constitutive COX - in the 2 expression and precancerous lesions Lung cancer is established, COX in chemoprevention - 2 inhibitors has led to Taste. Mao et al reported the feasibility of celecoxib as a chemopreventative By providing a heavy smoker, and factors for lung cancer 6 months of program implementation in serial bronchoscopy and bronchial and oral celecoxib Washing and biopsies (131). Treatment with celecoxib significantly 35% (P = 0016) Ki in smokers - 67 labeling index increased with decreasing Without significant change, nuclear survivin expression 23% (P = 0036),
Its cytoplasmic survivin. These findings supported the hypothesis that oral Shape of celecoxib Ki - 67 labeling index for Bronchial tissue of smokers at high risk of developing lung cancer. Maximum Randomization is underway to determine the efficacy, placebo-controlled clinical trials COX to prevent the development of lung cancer - 2 inhibitors
(132, 133). Several recent studies evaluated the inhibition of EGFR binding And COX - pathway in patients with non-small cell lung cancer was established 2. Gadgeel from the Phase II report of celecoxib and gefitinib in patients with platinum-resistant Non-small cell lung cancer (134,135). Patients daily gefitinib 250mg, 400mg celecoxib received Twice a day. The answer was a combination of gefitinib and celecoxib for Similar to those observed with gefitinib alone. Agarwala they are conducted A similar study in a selected population of patients with chemotherapy-naive Advanced non-small cell lung cancer (136). Again, the combination of gefitinib 250mg daily Did not increase the responsiveness and efficiency of celecoxib 400 mg twice daily Control treatment. O'Byrne et al reported a Phase I / II of the combination Daily gefitinib 250mg, rofecoxib 50mg daily treatment of patients Platinum - NSCLC recurrence of pre-treatment (137). Gefitinib in combination with rofecoxib
Discovered for disease control rate similar to what is expected to supply a single agent
Gefitinib. Finally, from Fiddler recently to assess the safety, Efficacy of erlotinib 150mg daily plus celecoxib 400mg twice daily facility Advanced non-small cell lung cancer (138). Combination therapy was superior to erlotinib In. But it is not only selected patients had longer progression-free survival Research suggests that combination, COX - 2 was observed in patients with large amounts of COX - would be more appropriate in the patient population was selected for two high volume Expression. Lack of benefit of the combination of EGFR tyrosine kinase These studies (TKI) COX and - 2 inhibitor, raised the question COX - whether the OBD system has been achieved to inhibit 2, whether a higher dose Have a significant impact on effectiveness. Reckamp and colleagues, the implementation of Phase I trials of increased Celecoxib in combination with fixed dose of erlotinib (200 〜 twice daily 800 mg) In patients with advanced NSCLC (date of 150 mg /), to establish the OBD of 600mg twice Every day, the maximum decrease in urinary prostaglandin EM (PGE - M) is defined by (139). This study showed an acceptable toxicity profile in combination
Disease showed a higher than expected for the erlotinib alone.
Based on these results, phase II trials are underway to evaluate a combination
Celecoxib compared with erlotinib 600 mg, 150 mg of daily
Erlotinib monotherapy. COX - 2 inhibitor use can improve the effectiveness of the OBD
And combination therapy, may explain the lack of interest in several studies
COX - that is using low doses 2 inhibitors. COX in the OBD - 2 inhibitor use, but may promote the reaction, Treatment toxicity, COX - might be related to the use of two inhibitors
Inhibitors. Gridelli et al, the addition of rofecoxib (date of 50mg /) to evaluate the Subject or stage IIIB NSCLC IV (140,141) with gemcitabine. Commercial Due to rofecoxib, the group that the safe was closed early The highest incidence of myocardial ischemia in patients treated with rofecoxib Sun 50mg /. Cumulative meta-analysis of 18 randomized controlled trials, 11 Increased risk of myocardial infarction, and colleagues report in June observational studies, Rofecoxib (142) in patients taking infarction. Other studies have shown That rofecoxib has a higher risk of cardiovascular toxicity compared with celecoxib And risks, (143) may be dose-dependent. Solomon and colleagues found Rofecoxib is associated with had an increased incidence of cardiovascular toxicity And non-steroidal anti-inflammatory drugs celecoxib and rofecoxib compared with patients> 25 mg dose of low-dose (143) were associated with higher risk. These studies have shown COX - 2 inhibitors, may have other cardiovascular risk, you can determine the dose. Safety profile. It is ischemia of the heart, whether it occurs more rapidly is unknown. COX - 2 inhibitors alone, in combination with short-term use of targeted therapies or Or conventional chemotherapy. Critical interpretation and planning for the future of these studies Study, patients with the treatment of choice. Chang et al, comparing The relative effect of aspirin on colorectal cancer risk compared to
Within the tumor COX - 2 expression (144). The authors have found that regular use of aspirin COX - will decrease the risk of colorectal cancer that overexpressed inhibitors of 2
If either COX - 2 expression is not weak or nonexistent. Randomized Phase Phase II study to assess whether there has been enjoying a double suspension, or eicosanoids Both drugs in combination with chemotherapy only (celecoxib or zileuton) found The advantage of celecoxib in patients with lung cancer and chemotherapy alone COX - 2 (145) tumors expressed moderate to high. These studies, demonstration Minimal ideals, the importance of a more individualized approach to treatment, Risk - to improve the efficiency of clinical trials and future benefits.