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 (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

Sarcomas are a heterogeneous group of tumors, requiring different chemotherapeutic approaches. Recently, several regimens for metastatic tumors were evaluated with respect to the different responses to conventional chemotherapy of the various histologic subtypes of sarcomas. The impact of pharmacogenetics in the progress of chemotherapy appears to be crucial in defining the clinical response to many drugs, such as anthracycline or alkylating agents, that are widely used in treatment regimens for soft tissue sarcomas (STS) or sarcomas of the bone. Polymorphisms of metabolizing enzymes (e.g., cytochrome P450 and glutathione-S-transferase), transporter proteins (reduced folate carrier and P-glycoprotein) or target proteins (thymidylate synthase, methylenetetrahydrofolate reductase, dihydrofolate reductase, and c-KIT) may be responsible for an altered clinical outcome, in terms of both response and toxicity. The administration of new chemotherapeutic agents, such as imatinib for gastrointestinal tumors (GIST), requires the study of genetic polymorphisms possibly affecting the integrity of the target (c-KIT), which may provide valid information regarding possible developments of therapy. For STS and sarcoma of the bone, the genetic markers, which could be unambiguously predictive of the phenotypic profile of patients, are as yet undetermined.
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PMID:Sarcomas and pharmacogenetics. 1614 99

The reduced folate carrier (RFC) is the dominant route for the uptake of various antifolates including PT523, a potent dihydrofolate reductase inhibitor (Ki = 0.35 pM) and an excellent transport substrate of the RFC (Kt = 0.7 microM). Here, we describe the multiple mechanisms of RFC inactivation in human leukemia PT523-resistant cells originally harboring 3 RFC alleles. Cellular exposure to gradually increasing PT523 concentrations resulted in sublines displaying up to 3500-fold resistance to various hydrophilic antifolates that rely on RFC for their cellular uptake. Antifolate-resistant cells lost RFC gene expression (65%-99% loss) due to impaired promoter binding of various transcription factors that regulate RFC gene expression. Additionally, DNA sequencing revealed that PT523-resistant cells contained a cluster of 4 nearly consecutive mutations residing on a single RFC allele including L143P, A147V, R148G, and Q150Stop. Southern blot analysis established the loss of an RFC allele in PT523-resistant cells. These alterations resulted in markedly decreased RFC protein levels (approximately 80%-99% loss) and consequently impaired [3H]methotrexate transport (87%-99% loss). This study provides the first evidence that acquisition of PT523 resistance in human leukemia cells harboring 3 RFC alleles is due to multiple coexisting alterations including transcriptional silencing, inactivating mutations, and RFC allele loss.
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PMID:Coexistence of multiple mechanisms of PT523 resistance in human leukemia cells harboring 3 reduced folate carrier alleles: transcriptional silencing, inactivating mutations, and allele loss. 1636 80

Transport is required before reduced folates and anticancer antifolates [e.g., methotrexate (MTX)] exert their physiologic functions or cytotoxic effects. The folate/antifolate transporter with the widest tissue distribution and greatest activity is the reduced folate carrier (RFC). There is little evidence that RFC-mediated influx is posttranscriptionally regulated. We show that [(3)H]MTX influx in CCRF-CEM human childhood T-leukemia cells is potentiated up to 6-fold by exogenous 5-amino-4-imidazolecarboxamide riboside (AICAr) in a AICAr and MTX concentration-dependent manner. Metabolism to more biologically active polyglutamate forms is also potentiated for MTX and other antifolates. That potentiation of influx by AICAr is mediated by effects on the RFC is supported by analyses +/-AICAr showing (a) similarity and magnitude of kinetic constants for [(3)H]MTX influx; (b) similarity of inhibitory potency of known RFC substrates; (c) lack of potentiation in a CCRF-CEM subline that does not express the RFC; and (d) similarity of time and temperature dependence. Potentiation occurs rapidly and does not require new protein synthesis. Effects of specific inhibitors of folate metabolism and the time and sequence of AICAr incubation with cells suggest that both dihydrofolate reductase inhibition and metabolism of AICAr are essential for potentiation. Acute folate deficiency or incubation of CCRF-CEM with AICAr-related metabolites (e.g., adenosine) does not initiate potentiation. AICAr increases growth inhibitory potency of MTX and aminopterin against CCRF-CEM cells when both AICAr and antifolate are present for the first 24 hours of a 120-hour growth period. AICAr is the first small molecule that regulates RFC activity.
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PMID:5-amino-4-imidazolecarboxamide riboside potentiates both transport of reduced folates and antifolates by the human reduced folate carrier and their subsequent metabolism. 1658 11

Cellular uptake of hydrophilic antifolates proceeds via the reduced folate carrier whereas lipophilic antifolates enter cells by diffusion. Recently we have shown that transfectant cells overexpressing the mutant G482 ABCG2 displayed 120-6,250-fold resistance to hydrophilic antifolates than untransfected cells upon 4 h drug exposure, but lost almost all their antifolate resistance upon 72 h drug exposure (Shafran et al. in Cancer Res 65:8414-8422, 2005). Here we explored the ability of the wild type (WT) R482-as well as the mutant G482-and T482 ABCG2 to confer resistance to lipophilic antifolate inhibitors of dihydrofolate reductase (trimetrexate, piritrexim, metoprine and pyrimethamine) and thymidylate synthase (AG337, AG377 and AG331). Lipophilic antifolate resistance was determined using growth inhibition assays upon 72 h drug exposure. Cells overexpressing these mutant efflux transporters displayed up to 106-fold resistance to lipophilic antifolates relative to untransfected cells; this resistance was reversed by the specific and potent ABCG2 efflux inhibitor Ko143. In contrast, cells overexpressing the WT R482 ABCG2 exhibited either no or only a low-level of lipophilic antifolate resistance. These results provide the first evidence that overexpression of the mutant G482- and T482 but not the WT R482 ABCG2 confers a high-level of resistance to lipophilic antifolates. The high membrane partitioning of lipophilic antifolates along with the large confinement of ABCG2 to the plasma membrane suggest that these mutant ABCG2 transporters may possibly recognize and extrude lipophilic antifolates from the lipid bilayer. The potential implications to cancer chemotherapy as well as the mechanism of anticancer drug extrusion by these mutant exporters are discussed.
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PMID:Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates. 1661 49

Folates play a key role in one-carbon metabolism essential for the biosynthesis of purines, thymidylate and hence DNA replication. The antifolate methotrexate has been rationally-designed nearly 60 years ago to potently block the folate-dependent enzyme dihydrofolate reductase (DHFR) thereby achieving temporary remissions in childhood acute leukemia. Recently, the novel antifolates raltitrexed and pemetrexed that target thymidylate synthase (TS) and glycineamide ribonucleotide transformylase (GARTF) were introduced for the treatment of colorectal cancer and malignant pleural mesothelioma. (Anti)folates are divalent anions which predominantly use the reduced folate carrier (RFC) for their cellular uptake. (Anti)folates are retained intracellularly via polyglutamylation catalyzed by folylpoly-gamma-glutamate synthetase (FPGS). As the intracellular concentration of antifolates is critical for their pharmacologic activity, polyglutamylation is a key determinant of antifolate cytotoxicity. However, anticancer drug resistance phenomena pose major obstacles towards curative cancer chemotherapy. Pre-clinical and clinical studies have identified a plethora of mechanisms of antifolate-resistance; these are frequently associated with qualitative and/or quantitative alterations in influx and/or efflux transporters of (anti)folates as well as in folate-dependent enzymes. These include inactivating mutations and/or down-regulation of the RFC and various alterations in the target enzymes DHFR, TS and FPGS. Furthermore, it has been recently shown that members of the ATP-binding cassette (ABC) superfamily including multidrug resistance proteins (MRP/ABCC) and breast cancer resistance protein (BCRP/ABCG2) are low affinity, high capacity ATP-driven (anti)folate efflux transporters. This transport activity is in addition to their established facility to extrude multiple cytotoxic agents. Hence, by actively extruding antifolates, overexpressed MRPs and/or BCRP confer antifolate resistance. Moreover, down-regulation of MRPs and/or BCRP results in decreased folate efflux thereby leading to expansion of the intracellular folate pool and antifolate resistance. This chapter reviews and discusses the panoply of molecular modalities of antifolate-resistance in pre-clinical tumor cell systems in vitro and in vivo as well as in cancer patients. Currently emerging novel strategies for the overcoming of antifolate-resistance are presented. Finally, experimental evidence is provided that the identification and characterization of the molecular mechanisms of antifolate-resistance may prove instrumental in the future development of rationally-based novel antifolates and strategies that could conceivably overcome drug-resistance phenomena.
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PMID:Molecular basis of antifolate resistance. 1733 44

This study investigated associations between CpG island methylator phenotype (CIMP) colon cancer and genetic polymorphisms relevant to one-carbon metabolism and thus, potentially the provision of methyl groups and risk of colon cancer. Data from a large, population-based case-control study (916 incident colon cancer cases and 1,972 matched controls) were used. Candidate polymorphisms in methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), transcobalamin II (TCNII), methionine synthase (MTR), reduced folate carrier (RFC), methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), dihydrofolate reductase (DHFR) and alcohol dehydrogenase 3 (ADH3) were evaluated. CIMP- or CIMP+ phenotype was based on five CpG island markers: MINT1, MINT2, MINT31, p16 and MLH1. The influence of specific dietary factors (folate, methionine, vitamin B(12) and alcohol) on these associations was also analyzed. We hypothesized that polymorphisms involved in the provision of methyl groups would be associated with CIMP+ tumors (two or more of five markers methylated), potentially modified by diet. Few associations specific to CIMP+ tumors were observed overall, which does not support the hypothesis that the provision of methyl groups is important in defining a methylator phenotype. However, our data suggest that genetic polymorphisms in MTHFR 1,298A > C, interacting with diet, may be involved in the development of highly CpG-methylated colon cancers. AC and CC genotypes in conjunction with a high-risk dietary pattern (low folate and methionine intake and high alcohol use) were associated with CIMP+ (OR = 2.1, 95% CI = 1.3-3.4 versus AA/high risk; P-interaction = 0.03). These results provide only limited support for a role of polymorphisms in one-carbon metabolism in the etiology of CIMP colon cancer.
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PMID:Genetic polymorphisms in one-carbon metabolism: associations with CpG island methylator phenotype (CIMP) in colon cancer and the modifying effects of diet. 1744 6

Antifolates that inhibit the key enzymes thymidylate synthase (TS) and dihydrofolate reductase (DHFR) have found clinical utility as antitumor and antiopportunistic agents. Methotrexate {MTX, (1)} and 5-fluorouracil (5-FU) were among the first clinically useful DHFR and TS inhibitors, respectively. The development of resistance to 5-FU, its occasional unpredictable activity and toxicity resulted in the search of novel antifolates. Pemetrexed (4) and raltitrexed (5) specifically inhibit TS, and are clinically useful as antitumor agents. A major mechanism of tumor resistance to clinically useful antifolates is based on their need for polyglutamylation via the enzyme folylpoly-gamma-glutamate synthetase (FPGS). Novel antifolates have been developed that do not need to be polyglutamylated and include plevitrexed (6) and GW1843 (7). Nonclassical antifolates for antitumor and parasitic chemotherapy, such as nolatrexed (8), trimethoprim {TMP, (11)} and piritrexim {PTX, (12)}, can passively diffuse into cells and hence do not have to depend on FPGS or the reduced folate carrier (RFC). Variations in the structures of antifolates have helped delineate the structural influence on the interaction with TS, DHFR, FPGS, and RFC utilization. The differences in the active site of human and pathogen DHFR have also been exploited. The literature contains excellent reviews on the design and synthesis of antifolates prior to 1996. This two-part review discusses the design, synthesis and structural requirements for TS and DHFR inhibition and their relevance to antitumor and parasitic chemotherapy, since 1996. Monocyclic and 6-5 fused bicyclic antifolates will be discussed in Part I, while 6-6 bicyclic and tricyclic antifolates will be discussed in Part II.
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PMID:Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: part I. 1789 13

Murine L1210 leukaemia cells expressing either the reduced folate carrier (RFC) or the membrane folate receptor (MFR) were studied in vitro and in vivo to assess the dynamics of membrane transport of two categories antifolates; folate-based inhibitors of dihydrofolate reductase (methotrexate, edatrexate, aminopterin, PT523, and PT644) and thymidylate synthase (TS) [CB3717, raltitrexed, plevitrexed (BGC9331), pemetrexed and GW1843]. The potency of in situ inhibition of TS was used as an endpoint to analyze the in vitro dynamics of RFC/MFR-membrane transport of these antifolates. Both for L1210-RFC and L1210-MFR cells, the potency of in situ TS inhibition was closely correlated with increasing affinities of these transporters for the antifolates (r = 0.64, P < 0.05 and r = -0.65, P < 0.05, respectively). Within the group of antifolates for which MFR had a low binding affinity, those that had the ability to become polyglutamylated, were more potent inhibitors of TS in situ activity than non-polyglutamatable antifolates. In vivo activity of methotrexate, edatrexate, raltitrexed and pemetrexed was assessed in L1210-RFC and L1210-MFR bearing mice that were fed either a standard or a folate-deficient chow. Dietary folate depletion significantly reduced the MTD for methotrexate (sevenfold), edatrexate (sevenfold), raltitrexed (50-fold) and pemetrexed (150-fold). Based on increased life spans, antitumor effects of methotrexate and edatrexate were markedly better in L1210-RFC bearing mice on the folate-deficient chow (ILS: 455 and 544%, respectively) than on standard chow (ILS: 213 and 263%, respectively). No therapeutic effects of methotrexate and edatrexate were observed for L1210-MFR bearing mice on either chow condition, which may be consistent with the low binding affinity for MFR. Irrespective of the folate diet status, pemetrexed and raltitrexed were inactive against both L1210-RFC and L1210-MFR bearing mice, which may be due to high circulating plasma thymidine levels. Collectively, this study underscores that modulation of dietary folate status can provide a basis within which the therapeutic effect of antifolates may be further improved.
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PMID:Dynamics of antifolate transport via the reduced folate carrier and the membrane folate receptor in murine leukaemia cells in vitro and in vivo. 1828 61

Antifolates that inhibit the key enzymes thymidylate synthase (TS) and dihydrofolate reductase (DHFR) have found clinical utility as antitumor and antiopportunistic agents. Methotrexate {MTX, (1)} and 5-fluorouracil (5-FU) were among the first clinically useful DHFR and TS inhibitors, respectively. The development of resistance to 5-FU, its occasional unpredictable activity and toxicity resulted in the search of novel antifolates. Pemetrexed (4) and raltitrexed (5) are newer antifolates that specifically inhibit TS, and are clinically useful as antitumor agents. A major mechanism of tumor resistance to clinically useful antifolates is based on their need for polyglutamylation via the enzyme folylpoly-gamma-glutamate synthetase (FPGS). Recently, classical antifolates that do not need to be polyglutamylated have also been developed and include plevitrexed (6) and GW1843 (7). Nolatrexed (8), trimethoprim {TMP, (11)} and piritrexim {PTX, (12)} are nonclassical antifolates for antitumor and parasitic chemotherapy that passively diffuse into cells and hence do not have to depend on FPGS or the reduced folate carrier (RFC). Structural requirements for inhibition with antifolates have been studied extensively and novel agents that exploit key interactions in the active site of TS, DHFR, FPGS, and RFC have been proposed. This two-part review discusses the design, synthesis and structural requirements for TS and DHFR inhibition and their relevance to antitumor and parasitic chemotherapy, since 1996. Monocyclic and 6-5 fused bicyclic antifolates were discussed in Part I. The 6-6 bicyclic and tricyclic antifolates will be discussed here in Part II.
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PMID:Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: Part II. 1828 23


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