Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Folic acid (PteGlu)-enhanced intense synergy has been observed between nonpolyglutamylatable dihydrofolate reductase (DHFR) inhibitors and polyglutamylatable inhibitors of other folate-requiring enzymes, such as glycinamide ribonucleotide formyltransferase (GARFT) and thymidylate synthase. Since this phenomenon is potentially therapeutically useful, we explored its universality by examining the combined action of a DHFR inhibitor, trimetrexate (TMQ), with a GARFT inhibitor, 4-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4,6][1,4]++ +thiazin-6-yl)-(S)-ethyl]-2,5-thienoylamino-L-glutamic acid (AG2034), in eight human cultured cell lines. Using a 96-well plate cell growth inhibition assay, four ileocecal adenocarcinoma cell lines [HCT-8, HCT-8/DW2 (Tomudex-resistant), HCT-8/DF2 (Tomudex-/FdUrd-resistant), and HCT-8/50 (adapted to 50 nM PteGlu)], three head and neck carcinoma cell lines [A253, FaDu, and Hep-2/500 (FdUrd-resistant)], and a non-small cell lung carcinoma cell line [H460] were treated for 96 hr with TMQ + AG2034 in the presence of 23 or 40 microM PteGlu. Cell growth was measured with the sulforhodamine B assay at the end of this period. Drug interactions were assessed by fitting a 7-parameter model including a synergism parameter, alpha, to data with weighted nonlinear regression. Isobologram analysis was also applied. At 23 microM PteGlu, cells exhibited similar intensities of Loewe synergy for the combination of TMQ + AG2034. Loewe synergy was abolished in HCT-8/50 cells cultured and studied in 50 nM PteGlu. At 40 microM PteGlu, the intensity of the combined action in all cell lines was increased However, the most intense Loewe synergy was seen with HCT-8, HCT-8/DF2, H460, FaDu, A253, and Hep-2/500 cells, whereas the HCT-8/50 subculture showed less of the phenomenon, and PteGlu enhancement was the least with HCT-8/DW2, a subline deficient in folylpolyglutamate synthetase (FPGS). The universality of the PteGlu-enhanced intense synergy phenomenon is suggested. Impaired FPGS activity and low-folate adaptation prior to treatment significantly lessen the degree of PteGlu enhancement.
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PMID:Folic acid-enhanced synergy for the combination of trimetrexate plus the glycinamide ribonucleotide formyltransferase inhibitor 4-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4,6][1,4]thiazin -6-yl)-(S)-ethyl]-2,5-thienoylamino-L-glutamic acid (AG2034): comparison across sensitive and resistant human tumor cell lines. 995 21

An important component in the development of a new anticancer drug is an understanding of its potential for inclusion in combination treatment regimens. LY231514, a multitargeted antifolate (MTA), was tested in combination with cisplatin, methotrexate, 5-fluorouracil, paclitaxel, docetaxel, doxorubicin, LY329201 (a glycinamide ribonucleotide formyltransferase [GARFT] inhibitor), and fractionated radiation therapy in vivo using EMT-6 mammary carcinoma, human HCT 116 colon carcinoma, and human H460 nonsmall cell lung carcinoma grown as xenografts in nude mice. Isobologram methodology was used to determine the additivity or synergy of the combination regimens. MTA administered with cisplatin, paclitaxel, docetaxel, or fractionated radiation therapy produced additive to greater than additive tumor response by tumor cell survival assay and tumor growth delay. While an additive tumor response was observed when MTA was administered with methotrexate, synergistic tumor responses were seen when MTA was administered with the GARFT inhibitor, LY329201, or with the topoisomerase I inhibitor, irinotecan. MTA was administered in combination with full doses of each anticancer agent studied, with no evidence of increased toxicity resulting from the combination.
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PMID:MTA (LY231514) in combination treatment regimens using human tumor xenografts and the EMT-6 murine mammary carcinoma. 1059 56

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.
Lung Cancer 2001 Dec
PMID:Gemcitabine and pemetrexed disodium combinations in vitro and in vivo. 1174 12

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

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.
Clin Lung Cancer 2004 Apr
PMID:Pharmacology and mechanism of action of pemetrexed. 1511 25

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.
Clin Lung Cancer 2008
PMID:New data integrating multitargeted antifolates into treatment of first-line and relapsed non-small-cell lung cancer. 1941 26