Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:New data integrating multitargeted antifolates into treatment of first-line and relapsed non-small-cell lung cancer. 1941 26

Pemetrexed is a newer antifolate drug that has been approved as first-line treatment for patients with advanced non-squamous, non-small cell lung cancer (NSCLC) in combination with cisplatin, and as single agent for relapsed or chemotherapy refractory NSCLC after platinum-containing chemotherapy, at a dose of 500 mg/m(2). Pemetrexed undergoes intracellular activation by poly-gamma-glutamylation, that is essential for its antiproliferative activity. Polyglutamate derivatives mainly inhibit three key enzymes of intracellular folate metabolism, i.e. thymidylates synthase (TYMS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), with TYMS being the most relevant target. Pemetrexed undergoes rapid renal elimination as unchanged parent compound, with a terminal half-life of between two to five hours. In later clinical development, the usefulness of supplementation with folic acid and vitamin B(12) became evident, to control pemetrexed-related toxicity. The results from the phase III upfront registration study, a retrospective observational data, and a recent maintenance study of pemetrexed in NSCLC suggest histological subtype to be the most important predictive marker for clinical outcome in patients receiving pemetrexed, Pemetrexed is active in patients with non-squamous cell NSCLC while no benefit is seen in patients with squamous-cell histology, possibly as a result of different expression of intratumoral TYMS. These are important steps towards individualisation of anticancer treatment in patients with advanced NSCLC.
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PMID:The role of pemetrexed in advanced non small-cell lung cancer: special focus on pharmacology and mechanism of action. 1983 29

Pemetrexed (PEM), a multitargeted antifolate with manageable toxicity, is active against non-squamous non-small cell lung cancer; however, most patients eventually acquire resistance to PEM. To elucidate the resistant mechanism, we established PEM-resistant lung adenocarcinoma cell lines. Two parental cell lines, PC-9 and A549, were treated with step-wise increasing concentrations of PEM. Growth inhibition was determined by the 3-[4,5-dimethyl-thizol-2-yl]-2,5-diphenyltetrazolium bromide assay. Expression of the genes encoding thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT) was analyzed by quantitative real-time reverse transcriptase polymerase chain reaction. The four PC-9 sublines were more resistant than the PC-9 cell line to PEM (2.2-, 2.9-, 8.4-, and 14.3-fold, respectively). The four A549 sublines also showed more resistance to PEM (7.8-, 9.6-, 42.3-, and 42.4-fold, respectively) than the parent cell line. All resistant sublines showed cross-resistance to cisplatin, but not to docetaxel, vinorelbine, 5-fluorouracil, or the active metabolite of irinotecan, SN-38. All PEM-resistant sublines expressed more TS than the parental cells, by polymerase chain reaction and Western blotting. DHFR was significantly increased in the four PEM-resistant A549 sublines. GARFT did not correlate with resistance to PEM. In summary, PEM-resistant cells remained sensitive to docetaxel, vinorelbine, 5-fluorouracil, and irinotecan. TS expression appeared to be associated with resistance to PEM.
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PMID:Establishment of pemetrexed-resistant non-small cell lung cancer cell lines. 2174 32

Elevated homocysteine is a risk marker for several major human pathologies. Emerging evidence suggests that perturbations of folate/homocysteine metabolism can directly modify production of inflammatory mediators. Pemetrexed acts by inhibiting thymidylate synthetase (TYMS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). EA.hy 926 cells grown under low ("Lo") and high ("Hi") folate conditions were treated with pemetrexed. The concentrations of several intracellular folate derivatives were measured using LC-MRM/MS. Lo cells had lower total folate concentrations and a different distribution of the intracellular folate derivatives than Hi cells. Treatment with pemetrexed caused a decrease in individual folate analytes. Microarray analysis showed that several genes were significantly up or down-regulated in pemetrexed treated Lo cells. Several of the significantly up-regulated transcripts were inflammatory. Changes in transcript levels of selected targets, including C3, IL-8, and DHFR, were confirmed by quantitative RT-PCR. C3 and IL-8 transcript levels were increased in pemetrexed-treated Lo cells relative to Lo controls; DHFR transcript levels were decreased. In Lo cells, IL-8 and C3 protein concentrations were increased following pemetrexed treatment. Pemetrexed drug treatment was shown in this study to have effects that lead to an increase in pro-inflammatory mediators in Lo cells. No such changes were observed in Hi cells, suggesting that pemetrexed could not modify the inflammatory profile in the context of cellular folate sufficiency.
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PMID:Pemetrexed alters folate phenotype and inflammatory profile in EA.hy 926 cells grown under low-folate conditions. 2297 65

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 B12 and folate pools). Supplementation with vitamin B12 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/m2 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. 2814 44

Antifolates are a class of drugs effective for treating malignant pleural mesothelioma (MPM). The majority of antifolates inhibit enzymes involved in purine and pyrimidine synthesis such as dihydrofolate reductase (DHFR), thymidylate synthase (TYMS), and glycinamide ribonucleotide formyltransferase (GART). In order to select the most suitable patients for effective therapy with drugs targeting specific metabolic pathways, there is a need for better predictive metabolic biomarkers. Antifolates can alter global metabolic pathways in MPM cells, yet the metabolic profile of treated cells has not yet been clearly elucidated. Here we found that MPM cell lines could be categorized into two groups according to their sensitivity or resistance to pemetrexed treatment. We show that pemetrexed susceptibility could be reversed and DNA synthesis rescued in drug-treated cells by the exogenous addition of the nucleotide precursors hypoxanthine and thymidine (HT). We observed that the expression of pemetrexed-targeted enzymes in resistant MPM cells was quantitatively lower than that seen in pemetrexed-sensitive cells. Metabolomic analysis revealed that glycine and choline, which are involved in one-carbon metabolism, were altered after drug treatment in pemetrexed-sensitive but not resistant MPM cells. The addition of HT upregulated the concentration of inosine monophosphate (IMP) in pemetrexed-sensitive MPM cells, indicating that the nucleic acid biosynthesis pathway is important for predicting the efficacy of pemetrexed in MPM cells. Our data provide evidence that may link therapeutic response to the regulation of metabolism, and points to potential biomarkers for informing clinical decisions regarding the most effective therapies for patients with MPM.
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PMID:Metabolic Characterization of Antifolate Responsiveness and Non-responsiveness in Malignant Pleural Mesothelioma Cells. 3036 78


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