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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The search for new combination chemotherapeutic regimens for the treatment of non-small-cell lung cancer is motivated not only by the desire to increase the objective tumor response and survival rates, but also by the desire to reduce toxicity, decrease symptoms, and improve the psychological well-being of treated patients. At present, the overall phase II response rates with existing combination chemotherapeutic regimens are approximately 15% to 30%, and the median survival rates are about 8 to 9 months. The median 1-year survival rates are about 30% to 40%, while the 2-year survival rates are only about 10% to 15%. Thus, while we have made substantial progress in the treatment of this disease, the long-term outcome is still relatively bleak. This article reviews the results of a phase I trial with a new combination chemotherapeutic regimen (gemcitabine [Gemzar] and the novel antifolate, Alimta), and outlines the rationale for, and design of, an ongoing phase II trial.
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PMID:Gemcitabine/Alimta in locally advanced or metastatic non-small-cell lung cancer. 1096 Sep 46

Current agents for the treatment of non-small-cell lung cancer include gemcitabine (Gemzar), paclitaxel (Taxol), docetaxel (Taxotere), vinorelbine (Navelbine), and irinotecan (CPT-11, Camptosar). Experimental agents include pemetrexed (LY231514, Alimta) and tirapazamine. Molecular and biological therapies include angiogenesis inhibitors, epidermal growth factor receptor inhibitors, HER2/neu inhibitors, and inhibitors of ras activation and function. Doublet chemotherapy is currently the standard treatment for advanced non-small-cell lung cancer. In the past 2 years, randomized trials have shown that many of the new two-drug combinations used to treat non-small-cell lung cancer have equivalent efficacy. These combinations produce 1-year survival rates of about 35% and 2-year survival rates of about 15%. Toxicity rates vary but are sufficiently low as to make the development of three-drug combinations feasible. Preliminary studies from several phase I and II trials suggest that triplet therapy can improve survival beyond that of double therapy regimens.
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PMID:Triplet combination chemotherapy and targeted therapy regimens. 1130 45

Pemetrexed disodium is a potent new antifolate which inhibits many folate-dependent reactions that are essential for cell proliferation. Its primary target is thymidylate synthase but it also inhibits folate-dependent enzymes involved in purine synthesis. Cells that are resistant to antifolates are generally less resistant to pemetrexed, irrespective of the mechanism of resistance. Pemetrexed has shown good activity in preclinical models with human tumour cells and xenografts. In the majority of clinical trials of pemetrexed, the dose-limiting toxic effect is neutropenia; other side-effects are mostly gastrointestinal. Preclinical studies indicate that the toxic effects of pemetrexed can be reduced by dietary folate, resulting in an improved therapeutic index. Low folate status is also associated with higher levels of toxicity in patients. As a single agent pemetrexed has shown good activity against non-small-cell lung cancer, squamous-cell carcinoma of head and neck, colon cancer, and breast cancer, and it appears to be particularly active in combination with cisplatin against non-small-cell lung cancer and mesothelioma. Phase II and III studies are underway.
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PMID:Pemetrexed disodium, a novel antifolate with multiple targets. 1190 85

Pemetrexed is a novel antifolate that inhibits several folate-dependent enzymes in addition to thymidylate synthase. Such a drug may have theoretical advantages over fluoropyrimidines and specifically acting antifolates. Phase I studies identified a preferred schedule of an intravenous dose once every 3 weeks. Phase II studies showed a broad spectrum of activity in solid tumors (ie, non-small cell lung, colorectal, and pancreatic cancers) usually considered refractory to most antimetabolites. Binary combinations with cisplatin, carboplatin, and gemcitabine have proven feasible and show encouraging activity in lung cancer and mesothelioma. Problems of sporadic life-threatening toxicity identified in early studies of this and other antifolates have been resolved by the discovery that they were caused by functional folate deficiency and may be avoided by a low-dose nutritional supplement of folic acid and vitamin B(12). Pemetrexed is a promising new drug that should make a contribution to solid tumor oncology.
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PMID:Future directions in the development of pemetrexed. 1202 94

Lung cancer is the leading cause of cancer death in the United States and throughout the world. The overall 5-year survival rate for lung cancer is dismal: 14% in the United States and even lower in other parts of the world. Recent developments in the armamentarium of chemotherapeutic agents for lung cancer have shown that two-drug combinations improve survival, relieve symptoms, and improve quality of life; however, complete response rates are still approximately 1% in stage IV disease and less than 20% of advanced stage patients survive 2 years. Therefore, improved therapeutic agents that increase efficacy are sorely needed. Most lung cancers overexpress thymidylate synthase and a variety of genes involved in cell cycle regulation. Previous studies have shown that some inhibitors of DNA synthesis (eg, gemcitabine) can improve the survival of advanced lung cancer patients, especially when combined with other agents such as cisplatin. The multitargeted antifolate, pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) was developed because it inhibits multiple enzymes involved in DNA synthesis including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase. The early studies of pemetrexed showed that the important dose-limiting toxicities were myelosuppression, mucositis, and diarrhea, all of which are common with any antimetabolite. Subsequent studies described in this article will show that these toxicities can be significantly reduced by the use of vitamin supplementation with folate and B12, and that pemetrexed has considerable activity in non-small cell lung cancer and mesothelioma.
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PMID:Incorporation of pemetrexed (Alimta) into the treatment of non-small cell lung cancer (thoracic tumors). 1209 34

Chemotherapy for non-small cell lung cancer (NSCLC) has developed within the past decade into an important part of treatment with palliative aims as well as part of curative combined-modality treatment. Furthermore, second-line treatment has become an accepted part of the palliative approach as well. Pemetrexed (alimta) is one of the recently introduced agents that have been evaluated for efficacy against NSCLC. In single-agent phase II studies in previously untreated NSCLC, pemetrexed resulted in a response rate of around 20%. In combination with cisplatin, response rates of 40% were achieved. As a second-line single agent in-patients with early progression after first-line treatment, the response rate is 9%. Toxicity is mainly hematologic and can be reduced by supportive measures. Overall, pemetrexed is an active agent that further improves the chemotherapeutic options of physicians involved in the treatment of NSCLC.
Lung Cancer 2002 Nov
PMID:Activity of pemetrexed (alimta), a new antifolate, against non-small cell lung cancer. 1243 22

Pemetrexed (Alimta); Eli Lilly and Co., Indianapolis, IN, USA) is a unique multitargeted antifolate that inhibits at least three enzymes, thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase. This novel drug is being evaluated in a comprehensive clinical programme for use in both front-line and second-line therapies. It has shown broad activity in a number of solid tumours, including colon cancer, breast cancer, lung cancer, head and neck, cervical cancer and others. While a number of antifolates have been evaluated in clinical trials, further development has been stopped or delayed by the occurrence of life-threatening toxicities. Similar trends were also initially observed with pemetrexed as well, but investigators later showed that these toxicities could be minimised with folic acid and vitamin B(12) supplementation included in the treatment regimen. Preliminary data indicate that this supplementation does not hamper drug efficacy in most tumour types and in many cases, supplemented patients exhibit improved clinical outcome. Here, the current data for pemetrexed in treating thoracic malignancies are reviewed, with special focus on malignant pleural mesothelioma and non-small cell lung cancer.
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PMID:Pemetrexed and its emerging role in the treatment of thoracic malignancies. 1272 Apr 95

Pemetrexed (ALIMTA, MTA) is a novel thymidylate synthase (TS) inhibitor and has shown activity against colon cancer, mesothelioma and nonsmall-cell lung cancer. We induced resistance to Pemetrexed in the human colon cancer cell line WiDr by using a continuous exposure to stepwise increasing Pemetrexed concentrations (up to 20 microM) as well as a more clinically relevant schedule with intermittent exposure (up to 50 microM) for 4 hr every 7 days, resulting in WiDr variants WiDr-cPEM and WiDr-4PEM, respectively. However, using the same conditions, it was not possible to induce resistance in the WiDr/F cell line, a variant adapted to growth under low folate conditions. Mechanisms of resistance to Pemetrexed were determined at the level of TS, folylpolyglutamate synthetase (FPGS) and reduced folate carrier (RFC). WiDr-4PEM and WiDr-cPEM showed cross-resistance to the polyglutamatable TS inhibitor Raltitrexed (6- and 19-fold, respectively) and the nonpolyglutamatable TS-inhibitor Thymitaq (6- and 42-fold, respectively) but not to 5-fluorouracil. The ratios of TS mRNA:beta actin mRNA in WiDr-4PEM and WiDr-cPEM were 5-fold (P=0.01) and 18-fold (P=0.04) higher, respectively, compared to WiDr (ratio: 0.012). In addition, TS protein expression in the resistant WiDr variants was elevated 3-fold compared to WiDr, while the catalytic activity of TS with 1 microM dUMP increased from 30 pmol/hr/10(6) cells in WiDr cells to 2201 and 7663 pmol/hr/10(6) cells in WiDr-4PEM and WiDr-cPEM, respectively. The activity of FPGS was moderately decreased, but not significantly different in all WiDr variants. Finally, no evidence was found that decreased catalytic activity of RFC was responsible for the obtained Pemetrexed resistance. Altogether, these results indicate that resistance to Pemetrexed in the colon cancer cell line WiDr was solely due to upregulation of TS of which all related parameters (mRNA and protein expression and TS activity) were increased, rather than alterations in FPGS or RFC activity.
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PMID:Induction of resistance to the multitargeted antifolate Pemetrexed (ALIMTA) in WiDr human colon cancer cells is associated with thymidylate synthase overexpression. 1290 42

Pemetrexed (Alimta , LY231514) is a new multitargeted antifolate that inhibits several enzymes involved in the folate pathway. Pemetrexed is a potent inhibitor of thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated clinical activity in non-small-cell lung cancer (NSCLC) as well as in a broad array of other solid tumors including mesothelioma and breast, colorectal, bladder, cervical, gastric, and pancreatic cancer. In NSCLC, single-agent activity has been documented in the first- and second-line settings. Promising activity has also been demonstrated when pemetrexed is combined with cisplatin, vinorelbine, oxaliplatin, carboplatin, and gemcitabine. Low-level dietary supplement of folic acid and vitamin B12 has significantly improved the safety profile of pemetrexed without compromising its antitumor effect. In this review, the pharmacology and clinical activity of pemetrexed in NSCLC cancer is discussed.
Clin Lung Cancer 2003 Jul
PMID:The role of Pemetrexed (Alimta , LY231514) in lung cancer therapy. 1459 99

Pemetrexed (Alimta ) is a novel multitargeted antifolate that inhibits 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. In non-small-cell lung cancer (NSCLC), single-agent activity has been documented in the first- and second-line settings. Promising activity has also been demonstrated when pemetrexed is combined with cisplatin and gemcitabine. A pivotal phase III study in mesothelioma has been presented, indicating the superiority of pemetrexed in combination with cisplatin versus cisplatin alone in this disease. Approval for pemetrexed in combination with cisplatin in advanced mesothelioma is expected within the next 12 months. This review discusses the activity of pemetrexed in NSCLC.
Clin Lung Cancer 2003 Jan
PMID:Current data with pemetrexed (Alimta) in non-small-cell lung cancer. 1472 Mar 39


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