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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant mesothelioma is a refractory malignancy. Treatment for unresectable disease may provide a palliative benefit, but survival duration is impacted only minimally, if at all. Several newer agents, including difluorodeoxycytidine (gemcitabine) and pemetrexed disodium (LY231514, Alimta) appear to have activity against this neoplasm. Phase II data for combination regimens of gemcitabine and a platinum in mesothelioma patients have been encouraging. However, no phase III data are available to place these phase II results in true perspective. In phase I studies of a cisplatin/pemetrexed combination, objective responses occurred in several mesothelioma patients. This led to a phase II trial of pemetrexed alone in untreated mesothelioma patients and a randomized phase III trial of cisplatin alone versus pemetrexed/cisplatin. Phase II activity (15% partial response) was seen with single-agent pemetrexed. The phase III trial accrued over 450 patients. Primary analysis of the phase III data set has been completed and the results will be presented at the American Society of Clinical Oncology Meeting in May 2002.
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PMID:The evolving role of gemcitabine and pemetrexed (Alimta) in the management of patients with malignant mesothelioma. 1472 Mar 52

The novel antifolate pemetrexed targets multiple enzymes involved in folate metabolism, resulting in inhibition of DNA synthesis. Pemetrexed has shown antitumor activity in preclinical models against a variety of tumor types, including non-small cell lung cancer. Phase II studies have confirmed its single-agent activity and manageable toxicity profile, and pemetrexed has shown antitumor activity in combination with other chemotherapeutics, including gemcitabine, taxanes, platinums, and vinorelbine, in the first-line treatment of advanced non-small cell lung cancer. A large ongoing phase III trial is comparing the activity of pemetrexed versus docetaxel in the second-line setting. Supplementation with oral folic acid and vitamin B12 was shown to reduce pemetrexed-related toxicity and increase its therapeutic index. These data suggest that pemetrexed has significant activity in advanced non-small cell lung cancer and represents a new treatment option for patients with this disease.
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PMID:Pemetrexed for treatment of advanced non-small cell lung cancer. 1498 87

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

Malignant mesothelioma is an uncommon malignancy that is locally invasive and rapidly fatal. The majority of patients with mesothelioma are not candidates for curative surgical resection. Chemotherapy has yielded only modest results in these patients. Pemetrexed is a multitargeted antifolate that is being evaluated in many tumor types. Recent single-agent data and data in combination with cisplatin have suggested that pemetrexed has therapeutic benefits in patients with malignant mesothelioma. This article summarizes the data regarding pemetrexed in the treatment of malignant mesothelioma and the potential novel combinations involving the drug that may be used in the future for the treatment of the disease.
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PMID:Novel combinations using pemetrexed in malignant mesothelioma. 1511 27

Malignant pleural mesothelioma (MPM) is a rare tumor, but its annual incidence is rapidly increasing. While most patients have locally advanced disease at presentation, to date there is no proven standard chemotherapy for MPM that has shown to increase survival in randomized studies. Therefore, the development of new therapeutic agents is urgent for this disease. Alimta is a novel, multitargeted antifolate with activity as single agent in patients with MPM. Recently, a phase III trial showed that the combination of Alimta with cisplatin resulted in a significantly increased efficacy compared with cisplatin alone. In addition, vitamin supplementation reduced treatment associated toxicities with no apparent affect on activity. This review summarizes preclinical and clinical data to define the future role of Alimta in the treatment of patients with MPM.
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PMID:The role of Alimta in the treatment of malignant pleural mesothelioma: an overview of preclinical and clinical trials. 1526 44

Several new antimetabolites, administered alone or in combination, are changing the therapeutic landscape for thoracic cancer. Two-drug combinations involving these newer drugs are becoming the standard of care for non-small-cell lung cancer (NSCLC), largely due to improvements in survival rates, time to disease progression, and response rates as well as an improved safety profile. Gemcitabine (Gemzar) has elicited considerable interest in this disease, as a combination partner in chemotherapeutic regimens. Another promising agent is pemetrexed (Alimta), a folate-based inhibitor of thymidylate synthase. In preclinical development, pemetrexed both alone and in combination with other cytotoxic agents has exhibited activity across a broad range of tumor models, including NSCLC and mesothelioma. In clinical trials of patients with NSCLC, pemetrexed has been an effective, well-tolerated agent that can be used as monotherapy or in combination with other agents at full dose. In clinical trials of patients with mesothelioma, the combination of pemetrexed and cisplatin demonstrated a significant improvement in survival, response, and patient quality-of-life parameters. The principle toxicities of pemetrexed can be minimized by folate and vitamin B12 supplements.
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PMID:New investigative regimens and cytotoxic agents in thoracic cancers: gemcitabine and pemetrexed. 1533 53

The use of chemotherapy in the treatment of early and advanced non-small-cell lung cancer (NSCLC) has increased during the past decade. One of the main reasons for the increased acceptance of chemotherapy is the development of several new cytotoxic agents with a unique mechanism(s) of action and high single-agent activity, combined with a favorable toxicity profile. Pemetrexed (Alimta) is a novel antifolate that inhibits several enzymes involved in DNA synthesis (thymidylate synthase [TS], dihydrofolate reductase [DHFR], and glycinamide ribonucleotideformyltransferase [GARFT]). Pemetrexed's toxicity is markedly reduced by folic acid and vitamin B12 supplementation. The compound has been studied extensively in various tumor types, including NSCLC. In NSCLC, pemetrexed at 500 mg/m2, every 3 weeks, given i.v. over 10 minutes, has shown promising activity, and can safely be administrated with vitamin supplementation. After registration, single-agent pemetrexed will certainly add to the chemotherapeutic options available for pretreated patients and will most likely change significantly chemotherapy prescriptions in second-line chemotherapy. In first-line chemotherapy, the role of platinum-based and -free combination doublet chemotherapy with pemetrexed still needs to be defined. Phase II data indicate high efficacy combined with favorable toxicity for pemetrexed in combination with cisplatin, carboplatin (Paraplatin), oxaliplatin (Eloxatin), gemcitabine (Gemzar), and vinorelbine (Navelbine). This review summarizes the clinical experience obtained thus far during the early clinical development of pemetrexed in NSCLC.
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PMID:Pemetrexed: its promise in treating non-small-cell lung cancer. 1533 59

Bridge homologation of the previously reported classical two-carbon-bridged antifolates, a 5-substituted 2,4-diaminofuro[2,3-d]pyrimidine (1) [which is a 6-regioisomer of LY231514 (Alimta)] and a 6-subsituted 2-amino-4-oxopyrrolo[2,3-d]pyrimidine, afforded the three-carbon-bridged antifolates analogues 4 and 5, with enhanced inhibitory activity against tumor cells in culture (EC(50) values in the 10(-8)-10(-7) M range or less). These two analogues were synthesized via a 10-step synthetic sequence starting from methyl 4-bromobenzoate (14), which was elaborated to the alpha-chloromethyl ketone (8) followed by condensation with 2,6-diamino-pyrimidin-4-one (7) to afford the substituted furo[2,3-d]pyrimidine 9 and the pyrrolo[2,3-d]pyrimidine 10. Subsequent coupling of each regioisomer with diethyl-l-glutamate followed by saponification afforded 4 and 5. The biological results indicate that elongation of the C8-C9 bridge of the classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidine and 6-substituted 2-amino-4-oxopyrrolo[2,3-d]pyrimidine are highly conducive to antitumor activity in vitro, despite a lack of increase in inhibitory activity against the target enzymes. This supports our original hypothesis that truncation of the B-ring of a highly potent 6-6 ring system to a 6-5 ring system can be compensated by bridge homologation to restore the overall length of the molecule.
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PMID:Synthesis of classical, three-carbon-bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates. 1561 38

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

Malignant pleural mesothelioma (MPM) is a disease with a poor prognosis, related in part to the aggressiveness of this disease, and in part due to the lack of drugs that have demonstrated tumor activity. Historically, antifolates such as methotrexate have been the most active drugs in the treatment of mesothelioma. Newer antifolates have recently demonstrated higher efficacy than older regimens in the treatment of this rare disease. One of these agents, pemetrexed (Alimta), has been evaluated both as a single agent and as part of a combination regimen. Pemetrexed has been studied in three trials in patients with MPM, and two phase I trials included patients with MPM. In a phase II trial, pemetrexed was studied as a single agent in patients with MPM. Seven of 64 patients achieved partial responses, with a median overall survival of 10.7 months. A large, randomized, phase III trial was conducted to compare pemetrexed/cisplatin with cisplatin. The response rate was 41.3% compared with 16.7%, median survival was 12.1 months compared with 9.3 months, and 1-year survival was 50.3% vs 38% in the pemetrexed/cisplatin and cisplatin arms, respectively. The combination of pemetrexed/cisplatin also demonstrated superiority in quality of life and pulmonary functioning analysis when compared with cisplatin.
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PMID:Pemetrexed in malignant pleural mesothelioma. 1565 33


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