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)

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.
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PMID:Gemcitabine and pemetrexed disodium combinations in vitro and in vivo. 1174 12

Pemetrexed, a thymidylate synthase (TS) and transferase inhibitor, is in phase III trials with Eli Lilly as a potential treatment for several common solid tumors, including non-small cell lung cancer (NSCLC) and mesothelioma [321789], [410731]. Studies on pemetrexed have concluded that not only is the compound a TS inhibitor but also a potent inhibitor of human dihydrofolate reductase (DHFR). The results suggest that pemetrexed acts upon multiple intracellular targets and that the antitumor effect may be derived from its simultaneous inhibition of multiple folate-requiring enzymes [203662]: this compound has been designated as a multitargeted antifolate (MTA) [386680]. The drug also causes concentration- and time-dependent apoptosis [284380]. Other studies in which the 4-oxo group of the pyrimidine ring portion of pemetrexed was replaced with a hydrogen atom, demonstrated that the resulting analogs were potent DHFR inhibitors with very little activity against the enzymes glycinamide ribonucleotide formyltransferase (GARFT) and TS [310674]. In phase II European studies in 64 patients with advanced breast cancer, encouraging responses were seen in anthracycline-failure (23%) and anthracycline-refractory (19%) patients. Responses were observed in 28% of patients who had been previously treated with a taxane [326097]. Data from a phase II trial of pemetrexed (500 mg/m2 once every 21 days as a 10 min i.v. infusion) as a salvage therapy in advanced breast cancer showed that supplementation of the treatment regime with folic acid (FA) and vitamin B12 reduced its already manageable and tolerable toxicities [408821], [409650]. At doses of 500 mg/m2, the drug was also safely administered to 35 patients with impaired renal function [409953]. Phase I and II trials have shown that the main side effects include neutropenia, thrombocytopenia, mucositis, nausea and vomiting [203666], [272241]. Princeton University holds the patent rights to this drug under EP-00432677. In June 2001, Lilly expected to launch the product in 2003 [412318]. In February 1999, Lehman Brothers predicted launch of the drug in 2001 [319225]. In February 1999, Deutsche Bank predicted sales of $100 million in 2001 rising to $400 million in 2003 [316821]. In November 1999, Lehman Brothers estimated peak revenues in excess of $1 billion [348368]. By September 2001, Bear Stearns & Co predicted sales of $35 million in 2002, rising to $125 million in 2005 [422325].
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PMID:Pemetrexed disodium (Eli Lilly). 1176 66

Alimta is a new-generation antifolate with inhibitory activity against multiple enzymes, including thymidylate synthase, glycinamide ribonucleotide formyltransferase and dihydrofolate reductase. Alimta is undergoing broad phase II evaluation as a single agent, and preliminary results show responses in several tumor types, including breast carcinoma. Doxorubicin is often used in combination chemotherapy of breast cancer. Because the two drugs have mechanisms of action that might be complementary, we investigated a possible synergism between doxorubicin and Alimta on growth inhibition of ZR-75-1 human breast carcinoma cells. Cytostatic activity was evaluated using semi-automated MTT assays, and drug interactions were determined using CalcuSyn (Chou/Hayball) multiple drug effect analyses. The cells were exposed to Alimta or doxorubicin as single agents and combinations for 24 hours starting at the time of plating or for 72 hours starting 24 hours after plating with a total culture time of 96 hours. Preincubation with Alimta for 24 hours followed by exposure to doxorubicin for 72 hours resulted in highly synergistic activity, whereas the opposite sequence or simultaneous exposure produced mainly an additive response. DNA flow cytometry studies indicated that Alimta causes a build-up of cells near the G1/S interface after 24 hours of incubation. The data suggest that, to obtain maximal antitumor activity, Alimta should precede doxorubicin when the drugs are given in combination chemotherapy protocols.
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PMID:Sequence dependence of Alimta (LY231514, MTA) combined with doxorubicin in ZR-75-1 human breast carcinoma cells. 1184 74

Metastatic breast cancer is a chemotherapy-responsive disease, and significant palliation of cancer-related symptoms can be achieved with effective treatment. New treatments are needed because patients with metastatic breast cancer commonly out-live the effectiveness of currently available cytotoxic and hormonal treatments. Pemetrexed is a novel antimetabolite that inhibits three enzymes critical in purine and pyrimidine biosynthetic pathways: thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Several phase II studies of pemetrexed have showed objective response rates of more than 30% in minimally pretreated metastatic breast cancer patients and approximately 20% in more heavily pretreated patients. Pemetrexed is associated with limited toxicity when administered with folic acid and vitamin B(12) supplementation and is therefore a promising agent both for palliative treatment of metastatic disease and for incorporation into combination regimens for treating newly diagnosed metastatic and early-stage breast cancer.
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PMID:Pemetrexed: a promising new treatment for breast cancer. 1202 91

The novel agent pemetrexed inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Significant activity has been seen in completed phase II trials of pemetrexed in non-small cell lung cancer and breast cancer. Pemetrexed is also active in combination with other agents such as gemcitabine, cisplatin, and carboplatin. In addition, this agent shows promising activity in bladder, head and neck, esophageal, renal, and cervical carcinomas. Preliminary results of studies in these tumor types are reviewed.
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PMID:Pemetrexed in the treatment of selected solid tumors. 1202 93

Pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) is a novel antifolate/antimetabolite with activity in breast cancer and has well-defined molecular targets, including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. In a phase II trial in patients with T3-4, N0-2 breast cancer, expression of thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, p53, and c-erb-B2 (at the mRNA or protein level) is being examined before and 24 hours after the first dose of neoadjuvant pemetrexed and after three cycles of single-agent treatment to establish correlations of biomarker levels and changes with clinical outcome and toxicity. Full biomarker and clinical data are not yet available from this study; however, clinical responses to pemetrexed treatment have been observed in patients. Results of this trial should provide both an idea of the activity of neoadjuvant pemetrexed in breast cancer and information on biomarker association with clinical performance that can be used in the design of additional clinical studies to assess the predictive value of these markers.
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PMID:Pemetrexed: translational research in breast cancer. 1209 37

Premetrexed disodium (MTA) is a novel multitargeted antifolate that inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. It exhibits a broad spectrum of activity against several human tumor types including colorectal cancer. Therefore, we evaluated the anti-proliferative potential of MTA combined with drugs known to exert therapeutic activity against colon cancer, including 5-fluorouracil, oxaliplatin, and SN38, the active metabolite of irinotecan. The effects of MTA, alone or combined with one of theses 3 drugs, were investigated in parental human HT29 colon cancer cells and in 5-fluorouracil-resistant counterparts HT29-5FU cells. These drugs were administered either simultaneously or sequentially. Functional interactions between MTA, 5-fluorouracil, oxaliplatin, and SN38 were evaluated using median-effect plot analysis. The drug combination and sequence with optimal effects were evaluated in athymic mice bearing human HT29 tumor cell xenografts. Combinations of MTA with 5-fluorouracil required high concentrations to achieved additive and/or synergistic effects. Simultaneous exposure to MTA and oxaliplatin led to synergistic activity in both parental and 5-fluorouracil-resistant human HT29 colon cancer cells, leading to additive antitumor effects and minimal toxicity in athymic mice bearing HT29 cell tumors. Synergism between MTA and SN38 was also observed in both parental and 5-fluorouracil-resistant HT29 cells. These results argue in favor of clinical trials of chemotherapy combining MTA with oxaliplatin or irinotecan (CPT-11), for the treatment of patients with colon cancer.
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PMID:Pemetrexed disodium combined with oxaliplatin, SN38, or 5-fluorouracil, based on the quantitation of drug interactions in human HT29 colon cancer cells. 1211 32

Gemcitabine has modest antitumor activity in advanced pancreatic cancer. New agents are clearly needed. Pemetrexed (ALIMTA) is a novel antifolate that inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed has shown in vitro activity against pancreatic cancer cell lines. In a Phase I trial of pemetrexed, two patients with pancreatic cancer achieved partial responses on the once every 21 days schedule. A Phase II trial of pemetrexed in patients with advanced pancreatic cancer showed an objective response rate of 6%, a one year survival of 28%, and a mild toxicity profile. The combination of pemetrexed and gemcitabine is synergistic in vitro and was broadly active in a Phase I trial. The pemetrexed/gemcitabine combination was evaluated in a Phase II trial in 42 patients with advanced pancreatic cancer. The promising activity observed in this study has led to an ongoing international, randomized, Phase III trial in 520 patients comparing the pemetrexed/gemcitabine combination with gemcitabine alone.
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PMID:The pemetrexed/gemcitabine combination in pancreatic cancer. 1220 73

We have studied the molecular basis of drug resistance in human CCRF-CEM leukemia cells exposed to high dose intermittent pulses of novel polyglutamatable antifolates that target various folate-dependent enzymes. These include the dihydrofolate reductase (DHFR) inhibitors edatrexate, methotrexate and aminopterin, the thymidylate synthase (TS) inhibitors ZD1694 and GW1843, the glycinamide ribonucleotide formyltransferase (GARTF) inhibitor DDATHF as well as the multitargeted antifolate LY231514 inhibiting both TS, DHFR and GARTF. Fourteen antifolate-resistant sublines were isolated, 11 of which displayed a drug resistance phenotype that was based on impaired folylpoly-gamma-glutamate synthetase (FPGS) activity as these cell lines: 1) typically lost 90-99% of parental FPGS activity; 2) expressed 1.4-3.3-fold less FPGS mRNA (only 4 cell lines); 3) displayed up to 10(5)-fold resistance to polyglutamylation-dependent antifolates including ZD1694 and MTA; 4) retained sensitivity to polyglutamylation-independent antifolates including ZD9331 and PT523; 5) were up to 19-fold hypersensitive to the lipid-soluble antifolates trimetrexate and AG377; 6) had a normal or a small decrease in [(3)H]MTX transport; and 7) had a 2.1-8.3-fold decreased cellular folate pools and a consequently increased folate growth requirement. The remaining 3 antifolate-resistant sublines lost 94-97% of parental [(3)H]MTX transport and thus displayed a high level resistance to all hydrophilic antifolates. To screen for mutations in the hFPGS gene, we devised an RT-PCR single strand conformational polymorphism (SSCP) assay. RT-PCR-SSCP analysis and DNA sequencing showed that only a single FPGS-deficient subline harbored an FPGS mutation (Cys346Phe). Three-dimensional modeling of the human FPGS based on the crystal structure of Lactobacillus casei FPGS suggested that this mutation maps to the active site and interferes with the catalytic activity of the enzyme due to a putative bulky clash between the mutant Phe346 and a native Phe350 within alpha-helix A10 in a highly conserved C-terminal hydrophobic core. This was consistent with a 23-fold decreased affinity of the mutant Cys346Phe FPGS for L-glutamate. We conclude that decreased FPGS activity is a dominant mechanism of resistance to polyglutamylation-dependent novel antifolates upon a high-dose intermittent exposure schedule. The finding that cells may exhibit 5 orders of magnitude of resistance to polyglutamylation-dependent antifolates but in the same time retain parental sensitivity or hypersensitivity to polyglutamylation-independent antifolates or lipophilic antifolates offers a potentially promising treatment strategy in the overcoming of FPGS-based anticancer drug resistance.
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PMID:Loss of folylpoly-gamma-glutamate synthetase activity is a dominant mechanism of resistance to polyglutamylation-dependent novel antifolates in multiple human leukemia sublines. 1249 65

The novel antimetabolite pemetrexed inhibits the folate-dependent enzymes thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. This agent is broadly active in a wide variety of solid tumors, including non-small cell lung, breast, bladder, head and neck, and ovarian cancers, as well as mesothelioma. Gemcitabine is a pyrimidine nucleoside antimetabolite that is approved worldwide for the treatment of pancreatic and non-small cell lung cancers, and bladder cancer outside the United States. In addition, gemcitabine is active against a broad range of tumors including breast, ovarian, and other cancers. Preclinical studies have shown cytotoxic synergy when pemetrexed is combined with gemcitabine. Based on these data, a phase I study of this combination was performed that showed striking activity. Phase II studies of this combination are being performed in breast and non-small cell lung cancer. In addition, a phase III study in pancreatic cancer is ongoing.
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PMID:Preclinical and clinical studies with combinations of pemetrexed and gemcitabine. 1257 8


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