Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined enzymatic activities of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in non-small cell lung cancer (NSCLC) tissues to determine the relationship to tumor sensitivity to 5-fluorouracil (5-FU). TS and DPD activities were measured in 60 surgically resected primary NSCLC tissues using a TS-binding assay and a radioenzyme assay, respectively. In vitro tumor sensitivity to 5-FU was assayed using a collagen gel droplet embedded culture drug test (CD-DST). DPD activities slightly correlated with in vitro sensitivity to 5-FU (r=0.402,P=0.013), such that tumors with higher DPD activity were more resistant to 5-FU. In contrast, no correlation was observed in TS activities. Thus, it was suggested that only DPD activity in NSCLC tissues is a potential indicator in predicting tumor sensitivity to 5-FU. Based on these results, further study is needed to evaluate the clinical significance of these enzymes in 5-FU-based chemotherapy for patients with NSCLC.
Lung Cancer 2001 Dec
PMID:Thymidylate synthase and dihydropyrimidine dehydrogenase activities in non-small cell lung cancer tissues: relationship with in vitro sensitivity to 5-fluorouracil. 1171 38

Pemetrexed disodium (ALIMTA) is a novel antimetabolite that inhibits at least three folate-dependent enzymes, thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed disodium is broadly active in a wide variety of solid tumours, including non-small cell lung, breast, bladder, head and neck and ovarian cancers. Gemcitabine is a broadly active pyrimidine nucleoside antimetabolite, which is approved for the treatment of pancreatic and non-small cell lung cancers. Three preclinical studies have been reported that show cytotoxic synergy between gemcitabine and pemetrexed. Clinical activity with this combination has been observed in a phase I study, with partial responses in three of five patients previously treated for non-small cell lung cancer. An international phase II study of this combination in non-small cell lung cancer is ongoing.
Lung Cancer 2001 Dec
PMID:Gemcitabine and pemetrexed disodium combinations in vitro and in vivo. 1174 12

We investigated thymidylate synthase (TS) expression in tumor tissues and examined the relationship between TS expression and post-operative survival in patients with p-stage I adenocarcinoma of the lung. A total of 104 patients, who underwent complete resection for p-stage I adenocarcinoma of the lung, were retrospectively reviewed. TS expression in tumor tissues was evaluated by immunohistochemical staining using rhTS polyclonal antibody. The intensity of immunohistochemical staining was classified into four categories using a visual grading system from 0 to 3. The percentage of each grade of TS staining was 9.6% for Grade 0, 18.3% for Grade 1, 35.6% for Grade 2 and 36.5% for Grade 3. Five-year survival rates of patients with Grade 0 to Grade 3 were 90.0, 83.9, 70.3 and 73.7%, respectively with no significant difference among all groups (P=0.236). When divided into two groups, according to the intensity of the grade, 5-year survival rates of TS low expression group (Grade 0 and Grade 1) and TS high expression group (Grade 2 and Grade 3) were 86.1 and 72.0%, respectively, with a significant difference (P=0.048). In conclusion, high level of TS expression was associated with poor prognosis. Immunohistochemical evaluation of TS expression may be useful to predict survival after complete resection in p-stage I adenocarcinoma of the lung.
Lung Cancer 2002 Feb
PMID:Prognostic value of thymidylate synthase expression in patients with p-stage I adenocarcinoma of the lung. 1180 89

Pemetrexed disodium is an antimetabolite with multiple sites of action. It inhibits dihydrofolate reductase, thymidylate synthase, and glycinamide ribonucleotide formyl transferase (GARFT). As a single agent it is active against a variety of solid tumors. One phase II trial demonstrated a 14.5% response rate for single-agent pemetrexed disodium in patients with previously untreated mesothelioma. The combination of pemetrexed disodium and cisplatin was associated with very encouraging regression rates in mesothelioma patients treated as part of a phase I trial. A subsequent trial showed similarly encouraging activity (10 partial responses out of 25 evaluable patients [40%]) in mesothelioma patients treated with pemetrexed and carboplatin. A large, prospectively randomized, phase III trial of cisplatin alone versus cisplatin and pemetrexed with vitamin support has been completed. The findings will be presented at the 38th Annual Meeting of the American Society of Clinical Oncology in May 2002.
Lung Cancer 2002 Nov
PMID:Alimta (pemetrexed disodium): a multitargeted antifolate for the treatment of mesothelioma. 1243 31

Pemetrexed (Alimta , LY231514) is a new multitargeted antifolate that inhibits several enzymes involved in the folate pathway. Pemetrexed is a potent inhibitor of thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated clinical activity in non-small-cell lung cancer (NSCLC) as well as in a broad array of other solid tumors including mesothelioma and breast, colorectal, bladder, cervical, gastric, and pancreatic cancer. In NSCLC, single-agent activity has been documented in the first- and second-line settings. Promising activity has also been demonstrated when pemetrexed is combined with cisplatin, vinorelbine, oxaliplatin, carboplatin, and gemcitabine. Low-level dietary supplement of folic acid and vitamin B12 has significantly improved the safety profile of pemetrexed without compromising its antitumor effect. In this review, the pharmacology and clinical activity of pemetrexed in NSCLC cancer is discussed.
Clin Lung Cancer 2003 Jul
PMID:The role of Pemetrexed (Alimta , LY231514) in lung cancer therapy. 1459 99

Pemetrexed (Alimta ) is a novel multitargeted antifolate that inhibits 3 enzymes involved in folate metabolism and purine and pyrimidine synthesis. These enzymes are thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. This agent has broad antitumor activity in phase II trials in a wide variety of solid tumors. In non-small-cell lung cancer (NSCLC), single-agent activity has been documented in the first- and second-line settings. Promising activity has also been demonstrated when pemetrexed is combined with cisplatin and gemcitabine. A pivotal phase III study in mesothelioma has been presented, indicating the superiority of pemetrexed in combination with cisplatin versus cisplatin alone in this disease. Approval for pemetrexed in combination with cisplatin in advanced mesothelioma is expected within the next 12 months. This review discusses the activity of pemetrexed in NSCLC.
Clin Lung Cancer 2003 Jan
PMID:Current data with pemetrexed (Alimta) in non-small-cell lung cancer. 1472 Mar 39

Many experimental studies have revealed that enhanced thymidylate synthase (TS) expression is significantly correlated with higher proliferative activity of tumor cells, which may account for a poor prognosis of high-TS patients. However, only a few clinical studies have focused on the correlation between TS status and cell proliferation. Therefore, we assessed the correlation between TS expression and proliferative index (PI) as a marker of cell proliferation or p53 status in a total of 109 patients with completely resected pathologic stage I, non-small cell lung cancer (NSCLC). PI was defined as the percentage of tumor cells with positive staining against proliferative cell nuclear antigen (PCNA). The mean PIs of TS-high and TS-low tumors were 48.2% and 34.4% respectively, showing a significantly higher proliferative activity of TS-high tumor (P=0.020); when stratified according to histological type, the difference was significant in adenocarcinoma (P=0.038), but not in squamous cell carcinoma. There was no significant correlation between TS expression and p53 status. In conclusion, tumor cells with higher TS expression have higher proliferative activity in NSCLC, especially in adenocarcinoma.
Lung Cancer 2004 Feb
PMID:Expression of thymidylate synthase is correlated with proliferative activity in non-small cell lung cancer (NSCLC). 1473 34

Pemetrexed is a novel multitargeted antifolate that inhibits > or = 3 enzymes involved in folate metabolism and purine and pyrimidine synthesis. These enzymes are thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. This agent has broad antitumor activity in phase II trials in a wide variety of solid tumors, and is approved in combination with cisplatin for the therapy of malignant mesothelioma. In a recent phase III trial, pemetrexed demonstrated equivalent efficacy to docetaxel, but with significantly less toxicity, in second-line treatment of non-small-cell lung cancer. The most common and serious toxicities of pemetrexed--myelosuppression and mucositis--have been significantly ameliorated by folic acid and vitamin B12 supplementation. More important, vitamin supplementation has not been shown to adversely affect efficacy in some tumor types. Tumors with codeletion of the methylthioadenosine phosphorylase gene, as a consequence of p16 deletions, may be particularly sensitive to pemetrexed. In this review, the biochemistry and mechanism of action of pemetrexed are discussed.
Clin Lung Cancer 2004 Apr
PMID:Pharmacology and mechanism of action of pemetrexed. 1511 25

Malignant pleural mesothelioma is an aggressive but rare malignancy with a dismal prognosis. It is traditionally resistant to chemotherapy. Antifolate agents have recently shown promising data in the treatment of this malignancy. Pemetrexed is a multitargeted antifolate inhibitor of thymidylate synthase and other folate-dependent enzymes that has emerged as one of the most active agents in this disease. Several phase I/II trials of pemetrexed as a single agent or in combination with a platinum drug have demonstrated considerable activity in mesothelioma. In a recently published phase III randomized study, pemetrexed/cisplatin showed a significant improvement in survival, response rate, and quality of life compared with single-agent cisplatin. In addition, several trials reported that folic acid and vitamin B12 supplementation significantly reduced the toxicity observed with the use of pemetrexed without affecting the efficacy of the drug.
Clin Lung Cancer 2004 Apr
PMID:Pemetrexed alone and in combination with platinum compounds in the management of malignant mesothelioma. 1511 26

We examined 116 stage I-IIIA non-small-cell lung cancer (NSCLC) patients for intra-tumoral expression of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) using TaqMan reverse transcription polymerase chain reaction (RT-PCR) assay to clarify the correlation between gene expression and the efficacy of 5-fluorouracil (5-FU) in patients with NSCLC. Patients who were administered 5-FU alone after surgery comprised the 5-FU group (n = 30), and those who underwent only surgery comprised the control group (n = 86). When dichotomized at the mean TS and DPD mRNA level, patients with low-DPD tumors who were administered 5-FU had a significantly better prognosis than those who did not receive adjuvant treatment (p = 0.041). In addition, in the 5-FU group, 10 patients with both low-TS and low-DPD tumors have not had any relapse, whereas 8 of the 20 patients with either high-TS or high-DPD tumors developed distant metastasis after surgery. Based on these results, the quantitation of TS and DPD mRNA levels may predict the efficacy of 5-FU after surgery for patient with NSCLC.
Lung Cancer 2004 Aug
PMID:Thymidylate synthase and dihydropyrimidine dehydrogenase mRNA levels in tumor tissues and the efficacy of 5-fluorouracil in patients with non-small-cell lung cancer. 1524 90


<< Previous 1 2 3 4 Next >>