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)

Pemetrexed (ALIMTA) is a novel multitargeted antifolate that inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. This agent is broadly active in a wide variety of solid tumors, including breast cancer, bladder cancer, mesothelioma, non-small-cell lung cancer, pancreatic cancer and ovarian cancer. Pemetrexed has also shown clinically relevant activity in combination with gemcitabine. This combination has been, and continues to be evaluated for the treatment of a number of malignancies, including non-small cell lung and ovarian cancer. A recently published randomized trial of different sequences has identified the sequence of pemetrexed on day 1 followed by gemcitabine on day 1 and gemcitabine on day 8, every 21 days as the most efficacious and least toxic sequence.
 ...
PMID:Clinical studies of pemetrexed and gemcitabine combinations. 1680 59

The sensitivity to 5-fluorouracil (5-FU) has been reported to be associated with target molecule thymidylate synthase (TS), fluoropyrimidine-metabolising enzymes such as orotate phosphoribosyltransferase (OPRT), and dihydropyrimidine dehydrogenase (DPD). We performed an immunohistochemical study on the clinical significance of TS, OPRT, and DPD expression using 151 resected non-small-cell lung cancer (NSCLC) patients postoperatively treated with a combination of tegafur and uracil (UFT). Eighty-two carcinomas were TS-positive, 105 carcinomas were OPRT-positive, 68 carcinomas were DPD-positive. No correlation was observed in the HSCORE between the TS and OPRT expression (r=0.203), between the TS and DPD expression (r=0.098), or between the OPRT and DPD expression (r=0.074). Regarding the survival of NSCLC patients treated with UFT, the 5-year survival rate of patients with TS-negative tumours was significantly higher than that with TS-positive tumours (P=0.0133). The 5-year survival rate of patients with OPRT-positive stage II to III tumours was significantly higher than that with OPRT-negative stage II to III tumours (P=0.0145). In addition, the 5-year survival rate of patients with DPD-negative tumours was also significantly higher than that with DPD-positive tumours (P=0.0004). A Cox multivariate regression analysis revealed the TS status (hazard ratio 2.663; P=0.0003), OPRT status (hazard ratio 2.543; P=0.0005), and DPD status (hazard ratio 2.840; P<0.0001) to all be significant prognostic factors for the survival of resected NSCLC patients postoperatively treated with UFT.
 ...
PMID:Evaluations of biomarkers associated with 5-FU sensitivity for non-small-cell lung cancer patients postoperatively treated with UFT. 1688 Jul 81

There is substantial evidence that the decreased risk of lung cancer with high intake of vegetables and fruits is linked to folate as a specific nutrient. Functional polymorphisms in genes encoding one-carbon metabolism enzymes, methylenetetrahydrofolate reductase (MTHFR C677T and A1,298C), methionine synthase (MTR A2,756G), methionine synthase reductase (MTRR A66G) and thymidylate synthase, influence folate metabolism and thus might be suspected of impacting on lung cancer risk. We therefore conducted a case-control study with 515 lung cancer cases newly and histologically diagnosed and 1,030 age- and sex-matched non-cancer controls to clarify associations with these five polymorphisms according to lung cancer subtype. Gene-environment interactions with smoking and drinking habit and folate consumption were also evaluated by logistic regression analysis. None of the polymorphisms showed any significant impact on lung cancer overall risk by genotype alone, but on histology-based analysis increase in MTHFR 677T and 1,298C alleles was associated with reduced risk of squamous/small cell carcinoma (P = 0.029), especially among heavy smokers (P = 0.035), whereas the MTHFR 677TT genotype was linked to decreased risk for these subtypes among heavy drinkers (odds ratio = 0.17, 95% confidence interval: 0.03-0.98). In addition, we found interactions between the MTRR A66G polymorphism and smoking (P = 0.015) and the MTHFR A1,298C polymorphism and alcohol consumption (P = 0.025) for risk of lung cancer overall. In conclusion, the results suggest that MTHFR polymorphisms contribute to risk of squamous/small cell carcinomas of the lung, along with possible interactions among folate metabolism-related polymorphisms and smoking/drinking habits. Further evaluation is warranted.
 ...
PMID:Impact of one-carbon metabolism-related gene polymorphisms on risk of lung cancer in Japan: a case control study. 1746 11

The pemetrexed (Alimta) is a new generation antifolate prescribed in the treatment of mesothelioma in association with cisplatin and in the 2nd line treatment of locally advanced or metastatic non-small lung cancer. Pemetrexed is an original molecule, different from the other antifolates. On the opposite methotrexate, pemetrexed inhibits several enzymes involved in the synthesis of purines and pyrimidines, in particular thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase. Pemetrexed is transported in cells by three receptors, which make easier its cellular penetration. On the other hand, the polyglutamation of the product by the folylpolyglutamate synthetase increases considerably its activity notably towards the thymidylate synthase. Finally, unlike methotrexate, pemetrexed presents an atypical effect on cellular synchronisation. The wide spectre of activity of pemetrexed confers it a therapeutic advantage with regard to the other antifolates specific of one or other one enzymes. The clinical results show an anti-tumoral activity against non-small lung cancer and in mesothelioma and recently towards other solid tumours, in particular in head an neck, colon and mammary cancers.
 ...
PMID:[Pemetrexed: from preclinic to clinic]. 1784 83

Apoptotic cell death was induced in human lung cancer DMS114 cells by treatment with beta-hydroxyisovalerylshikonin (beta-HIVS), an ATP-noncompetitive inhibitor of protein tyrosine kinases. Changes in phosphoprotein profiles were analyzed by two-dimensional-polyacrylamide gel electrophoresis (2D-PAGE) after the cells were treated with beta-HIVS. One spot on the 2D gel showed a marked decrease in intensity and the corresponding protein was identified by mass spectrometry as dUTP nucleotidohydrolase (dUTPase). The beta-HIVS-induced decrease of dUTPase in the phosphoprotein fraction of DMS114 cells was confirmed using immunoblotting. Treatment of the cells with beta-HIVS-induced rapid reduction of dUTPase activity. An antioxidant N-acetyl-cysteine inhibited both the reduction of phosphorylated dUTPase and the induction of apoptosis by beta-HIVS treatment of DMS114 cells. Introduction of siRNA directed against dUTPase mRNA into DMS114 cells enhanced the susceptibility of beta-HIVS-induced apoptosis. Treatment of DMS114 cells with beta-HIVS and 5-fluorouracil, a specific inhibitor of thymidylate synthase used as a chemotherapeutic drug, revealed the synergistic effects of these drugs on the inhibition of cell growth. These results suggest that dUTPase activity is one of the crucial factors involved in apoptotic cell death in lung cancer cells.
 ...
PMID:A tyrosine kinase inhibitor, beta-hydroxyisovalerylshikonin, induced apoptosis in human lung cancer DMS114 cells through reduction of dUTP nucleotidohydrolase activity. 1807 28

Because the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib and the multitargeted antifolate pemetrexed are registered in the treatment of second-line non-small-cell lung cancer (NSCLC), empirical combinations of these drugs are being tested. This study investigated molecular mechanisms underlying their combination in six NSCLC cell lines. Cells were characterized by heterogeneous expression of pemetrexed determinants, including thymidylate synthase (TS) and dihydrofolate reductase (DHFR), and mutations potentially affecting chemosensitivity. Pharmacological interaction was studied using the combination index (CI) method, whereas cell cycle, apoptosis induction, and EGFR, extracellular signal-regulated kinases 1 and 2, and Akt phosphorylation were studied by flow cytometry, fluorescence microscopy, and enzyme-linked immunosorbent assays. Reverse-transcriptase polymerase chain reaction (RT-PCR), Western blot, and activity assays were performed to assess whether erlotinib influenced TS. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assays demonstrated that EGFR and k-Ras mutations were related to erlotinib sensitivity, whereas TS and DHFR expression were related to pemetrexed sensitivity. Synergistic cytotoxicity was found in all cells, most pronounced with pemetrexed + erlotinib (24 h) --> erlotinib (48 h) sequence (CI, 0.09-0.40), which was associated with a significant induction of apoptosis. Pemetrexed increased EGFR phosphorylation and reduced Akt phosphorylation, which was additionally reduced by drug combination (-70.6% in H1650). Erlotinib significantly reduced TS expression and activity, possibly via E2F-1 reduction, as detected by RT-PCR and Western blot, and the combination decreased TS in situ activity in all cells. Erlotinib and pemetrexed showed a strong synergism in NSCLC cells, regardless of their genetic characteristics. Induction of apoptosis, modulation of EGFR and Akt phosphorylation, and changes in the expression of critical genes involved in pemetrexed activity contribute to this synergistic interaction and support the clinical investigation of these markers.
 ...
PMID:Molecular mechanisms underlying the synergistic interaction of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, with the multitargeted antifolate pemetrexed in non-small-cell lung cancer cells. 1818 83

The enzymes thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyl transferase (OPRT) are involved in the metabolism of the anticancer drug 5-fluorouracil (FU). Expression of TS, DPD and OPRT in cancer tissue has been reported to be associated with sensitivity and/or resistance to 5-FU therapy. However, the role of TS, DPD and OPRT expression in lung cancer has not been fully established. Furthermore, among several measuring methods, it is not clear which method effectively predicts the response to 5-FU therapy. The aim of this study was to analyze the expression of 5-FU-related enzymes using enzyme-linked immunosorbent assay (ELISA) and to examine the correlation of ELISA and the results obtained using different measuring methods such as reverse transcript polymerase chain reaction (RT-PCR), immunohistochemistry, and enzymatic activity. Lung cancer specimens were obtained from 134 patients who underwent curative resection for lung cancer. As a pilot study, enzyme expression of 11 samples was measured using 4 different methods for DPD: RT-PCR, immunohistochemistry, enzymatic activity and ELISA. The relationships between pairs of results were compared, and then enzyme protein expression was measured using ELISA in 119 patients with adenocarcinoma. Of the 4 independent methods, the highest correlation was observed between protein expression measured by ELISA and enzyme activity. The correlation of gene expression and ELISA was also significant. The protein level in stage I adenocarcinoma measured using ELISA was 13.0+/-24.8 ng/mg protein for TS, 362.2+/-264.3 ng/mg protein for DPD and 4.5+/-2.0 ng/mg protein for OPRT. The predictive value of the enzymes for prognosis and the effectiveness of 5-FU was not determined as few recurrences were observed during the short follow-up period. In conclusion, ELISA is a simple and reliable method to measure key enzymes related to 5-FU therapy.
 ...
PMID:Expression of 5-fluorouracil-related enzymes in lung cancer: ELISA characterizes enzyme activity and messenger RNA expression. 1928 6

Non-small-cell lung cancer (NSCLC) represents approximately 80% of all lung cancers. With modern platinum- based combination regimens, overall median survival has reached 9-12 months. Antifolates are active against several solid tumors and hematologic malignancies. The cytotoxic action of antifolates is mainly related to their ability to inhibit several different folate-dependent enzymes involved in DNA synthesis. Pemetrexed is a novel multitargeted antifolate that inhibits at least 3 of the enzymes involved in purine and pyrimidine synthesis: thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). Pemetrexed was approved for the treatment of relapsed NSCLC as it produced equivalent response and survival rates and less toxicity compared with docetaxel. Pemetrexed in combination with platinum analogues or with gemcitabine showed equivalent clinical impact compared with standard combinations of platinum plus third-generation agents. We analyze the potential implications of pemetrexed's role in first-line chemotherapy of NSCLC as well as hints of differential cytotoxic action according to histology, new schedules of vitamin supplementation, and target enzymes expression levels. Issues of pharmacogenomics are becoming relevant in defining pemetrexed efficacy. Chemosensitivity was significantly linked to low levels of TS, GARFT, and DHFR in preclinical models. Consequently, the differential expression of TS according to histology might explain the different activity of pemetrexed according to histology, as recently postulated.
Clin Lung Cancer 2008
PMID:New data integrating multitargeted antifolates into treatment of first-line and relapsed non-small-cell lung cancer. 1941 26

Pemetrexed, a new cytotoxic agent, is a potent inhibitor of thymidylate synthase and other folate-dependent enzymes. Firstly, pemetrexed was approved in combination with cisplatin for the treatment of malignant pleural mesothelioma. Successively, it has been studied, as single-agent, in phase II and III trials for second-line therapy of non-small cell lung cancer (NSCLC). Based on these results, pemetrexed has been registered for the treatment of recurrent NSCLC. The next step was to test pemetrexed plus cisplatin versus gemcitabine plus cisplatin, as first-line therapy in advanced NSCLC patients, in a phase III, non-inferiority, randomized trial. This trial reported the pemetrexed plus cisplatin regimen to be not inferior, in terms of activity and efficacy, to the control arm but statistically better tolerated. The role of pemetrexed as maintenance therapy after first-line therapy for advanced NSCLC is currently being evaluated into a phase III trial. The consistency of the results of these recent studies has identified a predictive effect of NSCLC non-squamous histology for pemetrexed. To date, pemetrexed is registered, at the dose of 500 mg/m(2) on day 1 of a 3-week schedule, in combination with cisplatin, for first-line therapy and, as single-agent, for second-line treatment of patients with non-squamous NSCLC.This review shows the latest and indicates the future developments of pemetrexed in the treatment of advanced NSCLC patients.
Lung Cancer 2009 Nov
PMID:Pemetrexed in the treatment of advanced non-squamous lung cancer. 1957 16

Despite advances in anticancer treatment, lung cancer still has poor prognosis. Recently, a cancer stem cell (CSC) hypothesis has emerged describing a small subset of tumor cells with stem cell properties. CSCs found in many solid tumors express CD133 antigen on the cell surface. The presence of CSC is correlated with poor survival of patients with glioblastomas, colon or prostate cancers. In this study, we evaluated whether CD133 expression in non-small cell lung cancer (NSCLC) has a prognostic value in patients' survival. We also analyzed whether CD133 positivity of NSCLC correlates with the expression of resistance-related proteins, angiogenic factors, oncogenes, proliferative activity or apoptosis. CD133 expression was retrospectively examined in a total of 88 cases of previously untreated NSCLC by immunohistochemistry. We found no correlation between CD133 positivity or the amount of CD133(+) cells with NSCLC patients' survival, expression of oncogenes c-myc, c-N-ras, c-jun, c-fos, c-erbB1, c-erbB2 or p53, angiogenic factors VEGF, VEGFR-1, FGF, FGFR-1, tissue factor and with proliferative activity or apoptosis in NSCLC tissues. However, there was a significant association between the expression of resistance-related proteins glutathione S-transferase, thymidylate synthase, catalase, O(6)-methylguanine-DNA methyltransferase and p170 and CD133. Because CD133 expression is linked to a resistant phenotype, detection of CD133(+) cells may be useful to predict efficacy of cytotoxic therapy but CD133 is not a strong prognostic parameter for survival of patients with NSCLC.
 ...
PMID:CD133 is indicative for a resistance phenotype but does not represent a prognostic marker for survival of non-small cell lung cancer patients. 1967 44


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