Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.5.1.3 (dihydrofolate reductase)
5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Pharmacology and mechanism of action of pemetrexed. 1511 25

Pemetrexed (ALIMTA, LY231514, MTA) is a novel antimetabolite that inhibits at least three enzymes involved in the folate pathway. These enzymes are thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated clinical activity in non-small cell lung cancer as well as in a broad array of other solid tumors, including mesothelioma, breast, colorectal, bladder, cervical, gastric and pancreatic cancer. In non-small cell lung cancer, single-agent activity has been documented in the first- and second-line settings in Phase II and Phase III trials. Promising activity has also been demonstrated when pemetrexed is combined with platinum compounds (cisplatin, carboplatin, and oxaliplatin), vinorelbine, and gemcitabine. Low level dietary supplement of folic acid and vitamin B12 has significantly decreased the mucosal and bone marrow toxicity of pemetrexed without compromising its antitumor effect.
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PMID:Pemetrexed (ALIMTA), a novel multitargeted antineoplastic agent. 1521 74

The purpose of this report is to summarize information on pemetrexed (LY231514; MTA; Alimta; Eli Lilly and Company; Indianapolis, IN), a drug recently approved by the U.S. Food and Drug Administration (FDA). The review of the efficacy and safety of pemetrexed is summarized below. Pemetrexed is a pyrrolopyrimidine antifolate. It inhibits thymidylate synthase, glycinamide ribonucleotide formyltransferase, and dihydrofolate reductase. In a single, randomized, single-blind, multicenter phase III trial, the efficacy and safety of pemetrexed combined with cisplatin (Platinol; Bristol-Myers Squibb; Princeton, NJ) were compared with those of single-agent cisplatin in 448 patients with malignant pleural mesothelioma. Two hundred twenty-six patients were randomized to receive pemetrexed and cisplatin, while 222 patients were randomized to receive cisplatin alone. The primary study end point was survival. Median survival times were 12.1 months for the pemetrexed plus cisplatin treated arm and 9.3 months for the cisplatin alone arm. Pemetrexed causes myelosuppression. The most common adverse events were neutropenia, fatigue, leukopenia, nausea, dyspnea, and vomiting. On February 4, 2004, pemetrexed was approved by the FDA in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. The recommended dose of pemetrexed is 500 mg/m(2) administered as an i.v. infusion over 10 minutes on day 1 of each 21-day cycle together with cisplatin at a dose of 75 mg/m(2) infused over 2 hours beginning 30 minutes after the pemetrexed infusion. Patients must receive oral folic acid and vitamin B(12) injections prior to the start of therapy and continue these during therapy to reduce severe toxicities. Patients should also receive corticosteroids with chemotherapy to reduce the risk of skin rashes. Approval was based on superior survival as a clinical benefit.
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PMID:FDA drug approval summaries: pemetrexed (Alimta). 1547 32

Pemetrexed (Alimta) is a novel antimetabolite that inhibits the folate-dependent enzymes thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated activity in clinical trials in a variety of tumor types, including lung, breast, colon, mesothelioma, pancreatic, gastric, bladder, head and neck, and cervix. Pemetrexed is rapidly metabolized into active polyglutamate forms that are potent inhibitors of several tetrahydrofolate cofactor-requiring enzymes critical to the synthesis of purines and thymidine. Functionally, pemetrexed acts as a prodrug for its polyglutamate forms. Two different transporters are known to take extracellular folates, and some antifolates, into the cell. These are the reduced folate carrier and the folate receptor. One of the many attributes that make pemetrexed unique is that methodology has been developed to eliminate and control the many of its associated clinical toxicities. Multivariate analyses demonstrated that pretreatment total plasma homocysteine levels significantly predicted severe thrombocytopenia and neutropenia, with or without associated grade 3/4 diarrhea, mucositis, or infection. Routine vitamin B12 and folic acid supplementation have resulted in decreased frequency/severity of toxicities associated with pemetrexed without affecting efficacy, making this novel antifolate a safe and efficacious anticancer agent.
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PMID:Biochemical pharmacology of pemetrexed. 1565 31

Pemetrexed (Alimta) is a novel folate antimetabolite that primarily inhibits the enzymes thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyl transferase (GARFT), all of which are involved in pyrimidine and purine synthesis. In a phase II trial of patients with T3/4, N0-2 breast cancer, expression of thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT), p53, and c-erb-B2 (at the mRNA or protein level) was examined in tumor biopsy specimens before and 24 hours after the first dose of pemetrexed and after three cycles of single-agent treatment to establish correlations of biomarker levels and changes with clinical outcome and toxicity. Although final data are not available, initial indications are that clinical response may correlate with decreased or low TS expression. The results obtained from clinical data are supported by laboratory results in three cell lines (MDA-231, MCF-7, and ZR-75). These results suggest that in vitro transcript profiling to identify which genes are important predictors of successful cytotoxic chemotherapy, followed by a focused clinical trial to confirm the in vitro results, may be the best approach for translational research.
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PMID:Translational research with pemetrexed in breast cancer. 1565 41

Gemcitabine and pemetrexed are effective agents in the treatment of non-small-cell lung cancer (NSCLC), and the present study investigates cellular and genetic aspects of their interaction against A549, Calu-1, and Calu-6 cells. Cells were treated with pemetrexed and gemcitabine, and their interaction was assessed using the combination index. The role of drug metabolism in gemcitabine cytotoxicity was examined with inhibitors of deoxycytidine kinase (dCK), 5'-nucleotidase, and cytidine deaminase, whereas the role of pemetrexed targets, thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT) in drug chemosensitivity was analyzed in cytotoxicity rescue studies. The effect of gemcitabine and pemetrexed on Akt phosphorylation was investigated with enzyme-linked immunosorbent assay, whereas quantitative polymerase chain reaction (PCR) was used to study target gene-expression profiles and its modulation by each drug. Synergistic cytotoxicity was demonstrated, and pemetrexed significantly decreased the amount of phosphorylated Akt, enhanced apoptosis, and increased the expression of dCK in A549 and Calu-6 cells, as well as the expression of the human nucleoside equilibrative transporter 1 (hENT1) in all cell lines. PCR demonstrated a correlation between dCK expression and gemcitabine sensitivity, whereas expression of TS, DHFR, and GARFT was predictive of pemetrexed chemosensitivity. These data demonstrated that 1) gemcitabine and pemetrexed synergistically interact against NSCLC cells through the suppression of Akt phosphorylation and induction of apoptosis; 2) the gene expression profile of critical genes may predict for drug chemosensitivity; and 3) pemetrexed enhances dCK and hENT1 expression, thus suggesting the role of gene-expression modulation for rational development of chemotherapy combinations.
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PMID:Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells. 1579 20

Alimta (pemetrexed) is a novel multitargeted antifolate that inhibits several enzymes in the de novo pathways of pyrimidine and purine biosynthesis, including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed possesses antitumor activity in several solid tumors, including non-small cell lung cancer, malignant pleural mesothelioma, pancreas, colorectal, gastric, bladder, breast, and head and neck cancers. The main toxicities of the drug are myelosuppression, skin rash, and mucositis. Both myelosuppression and mucositis are more frequent in patients with high homocysteine plasma levels (an indicator of deficient vitamin B(12) and folate pools). Supplementation with vitamin B(12) and folic acid greatly reduces most severe toxicities and has been implemented in pemetrexed trials since December 1999. Pemetrexed has been tested in five phase II trials in locally advanced or metastatic breast cancer. The drug has shown an activity of around 30% in advanced breast cancer patients with minimal or no prior chemotherapy. In patients who received prior anthracyclines, response rates of 21% were reported. Responses have also been observed in a moderate proportion of patients who had been pretreated with anthracyclines, taxanes, and capecitabine. Some studies have suggested that a correlation exists between thymidylate synthase tumor expression with pemetrexed antitumor activity; this attractive hypothesis should be confirmed in further studies. The optimal dose when combined with vitamin supplementation is under current investigation in patients with breast cancer. A randomized phase II study comparing pemetrexed 600 and 900 mg/m(2) with vitamin supplementation as first-line treatment for metastatic breast cancer is ongoing.
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PMID:Clinical experience with pemetrexed in breast cancer. 1647 13

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.
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PMID:Clinical studies of pemetrexed and gemcitabine combinations. 1680 59

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.
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PMID:[Pemetrexed: from preclinic to clinic]. 1784 83

Pemetrexed (ALIMTA, LY231514) is a novel, multi targeted antifolate chemotherapy agent that is active in various tumors including mesothelioma, NSCLC, breast, colon and bladder carcinoma. Pemetrexed inhibits several enzymes in the folate pathway including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed is approved in the United States and a number of European Union countries for use in the treatment of mesothelioma, and the second-line treatment of advanced NSCLC. However, in Japan, pemetrexed was approved for use only in combination with cisplatin in the treatment of mesothelioma in January 2007. This approval was granted on the basis of a phase III trial of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. Treatment with pemetrexed plus cisplatin and vitamin supplementation, resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone. In addition, in a phase III trial of pemetrexed versus docetaxel in patients with NSCLC previously treated with chemotherapy, treatment with pemetrexed resulted in clinically equivalent efficacy outcomes, but with significantly fewer side effects including grade 3 or 4 neutropenia , neutropenic fever, and alopecia, compared with docetaxel. Therefore, pemetrexed should be considered a standard treatment option for second-line NSCLC in US and most of EU. Addition of folic acid and vitamin B12 significantly reduced the toxicity of pemetrexed, especially hematologic toxicity and gastrointestinal toxicity. Pemetrexed is the expected agent for use in high risk patients, especially elderly or poor performance status patients.
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PMID:[Pemetrexed]. 1863 41


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