Glutamyl hydrolase and the multitargeted antifolate LY231514

Rhee, Myung S.; Ryan, Thomas J.; Galivan, John

doi:10.1007/s002800051000

Cited by 29 publications

(13 citation statements)

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“…In contrast, sensitivity to MTA was not correlated with TS , FPGS or RFC gene expression or activity in colon cancer cell lines [34] and in gastric cancer cell lines [38] . It is likely that many factors, including other chemosensitivity-related factors we did not test, such as multidrug resistance proteins, glutamyl hydrolase [44] or an unidentified transport system [45] , may influence the sensitivity to MTA. Therefore, further examination is needed to establish a reliable method to predict chemosensitivity to MTA in an individual clinical case with NSCLC.…”

Section: Discussionmentioning

confidence: 99%

Schedule-Dependent Synergistic Effect of Pemetrexed Combined with Gemcitabine against Malignant Pleural Mesothelioma and Non-Small Cell Lung Cancer Cell Lines

Nagai

Takenaka²,

Sonobe³

et al. 2008

Chemotherapy

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Background: Pemetrexed, a multi-targeted antifolate (MTA), is a promising agent in the treatment of malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC). With the aim of finding an optimal schedule for the combination therapy of MTA and gemcitabine (GEM), we investigated their interaction against an MPM cell line, 211H, and the NSCLC cell lines A549 and H1299. Methods: Combination index analysis was used in 3 different schedules. Cell cycle analysis by flow cytometry and real-time RT-PCR analysis of thymidylate synthase (TS), folylpolyglutamate synthetase (FPGS) and reduced folate carrier 1 (RFC1) genes were performed to understand the biological consequences of their interaction. Results: MTA showed potent cytotoxicity against 211H cells (IC₅₀, 67 nM for 48 h exposure), compared to NSCLC cell lines. Significantly higher expression of FPGS and RFC1 mRNAs in 211H cells were associated with MTA sensitivity. Simultaneous exposure of MTA and GEM was antagonistic in all cell lines tested. Strong synergism was observed in 211H cells when MTA preceded GEM, but the inverted sequence showed antagonism. Similar results were exhibited in H1299 cells, whereas a moderately synergistic effect was observed in A549 cells when GEM preceded MTA. S phase accumulation by MTA treatment partly supported these results. Conclusion: Sequential administration of MTA and GEM is active, and the schedule of MTA followed by GEM is recommended for treating MPM.

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Section: Discussionmentioning

confidence: 99%

Schedule-Dependent Synergistic Effect of Pemetrexed Combined with Gemcitabine against Malignant Pleural Mesothelioma and Non-Small Cell Lung Cancer Cell Lines

Nagai

Takenaka²,

Sonobe³

et al. 2008

Chemotherapy

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“…Pemetrexed, a folate antimetabolite, has demonstrated activity in HCC cell lines in vitro [10], but cells overexpressing glutamyl hydrolase and thymidine synthetase are resistant to its effects [11]. Pemetrexed inhibits several enzymes, including thymidine synthetase, a target of 5-FU, glycinamide ribonucleotide formyltransferase, and dihydrofolate reductase, a target of methotrexate.…”

Section: Introductionmentioning

confidence: 98%

A phase II study of pemetrexed in patients with advanced hepatocellular carcinoma

Cohn¹,

Myers²,

Mamus³

et al. 2008

Invest New Drugs

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Pemetrexed has demonstrated activity in hepatocellular carcinoma (HCC) cell lines, and has a manageable toxicity profile in clinical trials, suggesting its potential as a treatment for HCC patients. A multicenter, Phase II community-based study was conducted to assess the response rate and toxicity profile of single-agent pemetrexed in first-line patients with advanced or metastatic HCC. Patients premedicated with folic acid, vitamin B(12), and dexamethasone were administered pemetrexed 600 mg/m(2) IV on day 1 of each 21-day cycle until disease progression. This nonrandomized study employed Simon's 2-stage design, enrolling 21 eligible patients in the first stage, stopping accrual if < or =2 responders were observed. Responses were four stable disease, 14 progressive disease, and three not evaluable: two had early toxicities (renal/liver failure, sepsis) and one was noncompliant. The most common grade 3 hematological toxicities were neutropenia 6 of 21 (29%) and thrombocytopenia 3 of 21 (14%); with no grade 4 toxicities. Thirteen patients died on-study: 12 PD and one liver failure; none were drug-related. The median survival was 5.2 months (range, <1-12.2). The planned second stage was cancelled, and the trial was closed owing to lack of response. While pemetrexed was tolerated in this patient population, it was not active.

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“…This turned out to be the case in several studies on acquired resistance to antifolates. For instance, a human H35 hepatoma cell line selected for resistance to DDATHF had a sevenfold increase in g-GH activity, but no change in FPGS activity (Rhee et al, 1993). The loss of g-GH activity resulted in resistance to 10-propargyl-5,8-dideazafolate for which transport was not impaired.…”

Section: Alterations In G-gh Activitymentioning

confidence: 99%