5,10-Methenyltetrahydrofolate synthetase activity is increased in tumors and modifies the efficacy of antipurine LY309887

Field, Martha S.; Anguera, Montserrat C.; Page, Rodney L.

doi:10.1016/j.abb.2008.11.001

Cited by 14 publications

(17 citation statements)

References 24 publications

(50 reference statements)

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“…In addition, two folate-dependent enzymatic activities in this pathway ( i.e. the activities of GAR transformylase (step 3) in TrifGART and aminoimidazolecarboxamide ribonucleotide transformylase (step 9) in ATIC) are considered as key targets for the development of antineoplastic agents, for example Lometrexol, LY309887, and Pemetrexed (Alimta) now in the clinic ( 28 ). Many of these drugs were designed primarily to perturb enzymatic activities on the basis of chemical structures resembling purines or precursors and may have additional effects on the context of the purinosome.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Regulation of a Metabolic Multi-enzyme Complex by Protein Kinase CK2

Kyoung

Allen

et al. 2010

Journal of Biological Chemistry

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The reversible association and dissociation of a metabolic multi-enzyme complex participating in de novo purine biosynthesis, the purinosome, was demonstrated in live cells to respond to the levels of purine nucleotides in the culture media. We also took advantage of in vitro proteomic scale studies of cellular substrates of human protein kinases (e.g. casein kinase II (CK2) and Akt), that implicated several de novo purine biosynthetic enzymes as kinase substrates. Here, we successfully identified that purinosome formation in vivo was significantly promoted in HeLa cells by the addition of small-molecule CK2-specific inhibitors (i.e. 4,5,6,7-tetrabromo-1H-benzimidazole, 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole, tetrabromocinammic acid, 4,4′,5,5′,6,6′-hexahydroxydiphenic acid 2,2′,6,6′-dilactone (ellagic acid) as well as by silencing the endogenous human CK2α catalytic subunit with small interfering RNA. However, 4,5,6,7-tetrabromobenzotriazole, another CK2-specific inhibitor, triggered the dissociation of purinosome clusters in HeLa cells. Although the mechanism by which 4,5,6,7-tetrabromobenzotriazole affects purinosome clustering is not clear, we were capable of chemically reversing purinosome formation in cells by the sequential addition of two CK2 inhibitors. Collectively, we provide compelling cellular evidence that CK2-mediated pathways reversibly regulate purinosome assembly, and thus the purinosome may be one of the ultimate targets of kinase inhibitors.

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Section: Discussionmentioning

confidence: 99%

Dynamic Regulation of a Metabolic Multi-enzyme Complex by Protein Kinase CK2

Kyoung

Allen

et al. 2010

Journal of Biological Chemistry

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“…pCMV6-DHFRL1-GFP and pCMV6-GFP vectors were linearized using ScaI (New England Biolabs), electroporated into CHO GlyC cells, and selected as previously described (11). Trypan blue exclusion assays were completed in media with and without glycine as previously reported (37).…”

Section: Methodsmentioning

confidence: 99%

Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria

Anderson

Quintero

Stover

2011

Proc. Natl. Acad. Sci. U.S.A.

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155

137

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The de novo and salvage dTTP pathways are essential for maintaining cellular dTTP pools to ensure the faithful replication of both mitochondrial and nuclear DNA. Disregulation of dTTP pools results in mitochondrial dysfunction and nuclear genome instability due to an increase in uracil misincorporation. In this study, we identified a de novo dTMP synthesis pathway in mammalian mitochondria. Mitochondria purified from wild-type Chinese hamster ovary (CHO) cells and HepG2 cells converted dUMP to dTMP in the presence of NADPH and serine, through the activities of mitochondrial serine hydroxymethyltransferase (SHMT2), thymidylate synthase (TYMS), and a novel human mitochondrial dihydrofolate reductase (DHFR) previously thought to be a pseudogene known as dihydrofolate reductase-like protein 1 (DHFRL1). Human DHFRL1, SHMT2, and TYMS were localized to mitochondrial matrix and inner membrane, confirming the presence of this pathway in mitochondria. Knockdown of DHFRL1 using siRNA eliminated DHFR activity in mitochondria. DHFRL1 expression in CHO glyC, a previously uncharacterized mutant glycine auxotrophic cell line, rescued the glycine auxotrophy. De novo thymidylate synthesis activity was diminished in mitochondria isolated from glyA CHO cells that lack SHMT2 activity, as well as mitochondria isolated from wild-type CHO cells treated with methotrexate, a DHFR inhibitor. De novo thymidylate synthesis in mitochondria prevents uracil accumulation in mitochondrial DNA (mtDNA), as uracil levels in mtDNA isolated from glyA CHO cells was 40% higher than observed in mtDNA isolated from wild-type CHO cells. These data indicate that unlike other nucleotides, de novo dTMP synthesis occurs within mitochondria and is essential for mtDNA integrity.folate | one-carbon metabolism | thymidine | deoxyribouridine

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“…There is also rationale for the use of antifols in primary CNS tumors such as ependymoma, which have been shown to have high expression of folate receptors. Because observational and preclinical data suggest that folates also play a role in neuroblastoma metabolism and occurrence [9][10][11][12], the use of antifol chemotherapy may have a role in its treatment as well. Fluorouracil is another antifol currently used in pediatric cancer for treatment of hepatoblastoma and nasopharyngeal carcinoma.…”

Section: Introductionmentioning

confidence: 99%

“…Sixty-eight were evaluable for response. The median number of cycles administered was 2 (range [1][2][3][4][5][6][7][8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Phase 2 trial of pemetrexed in children and adolescents with refractory solid tumors: A Children's Oncology Group study

Warwick

Malempati

Krailo

et al. 2012

Pediatric Blood & Cancer

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Background Pemetrexed is a multi-targeted antifolate that inhibits key enzymes involved in nucleotide biosynthesis. We performed a phase 2 trial of pemetrexed in children with refractory or recurrent solid tumors, including CNS tumors, to estimate the response rate and further define its toxicity profile. Procedure Pemetrexed, at a dose of 1910 mg/m2, was administered as a 10-minute intravenous infusion every 21 days. Patients also received vitamin B12, daily multivitamin supplementation, and dexamethasone. A two-stage design (10 + 10) was employed in each of the following disease strata: osteosarcoma, Ewing sarcoma/peripheral primitive neuroectodermal tumor (PNET), rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, and non-brainstem high-grade glioma. Results Seventy-two eligible subjects (39 males) were enrolled. Median age was 11 years (range 3–23). Sixty-eight were evaluable for response. The median number of cycles administered was 2 (range 1–13). No complete or partial responses were observed. Stable disease, for a median of 5 (range 4–13) cycles, was observed in 5 patients (ependymoma, Ewing sarcoma, medulloblastoma, neuroblastoma, osteosarcoma; n=1 each). Neutropenia (44%), anemia (35%), and elevated alanine transaminase (35%) attributable to pemetrexed were the most commonly recurring toxicities observed in patients receiving multiple cycles. Other toxicities attributed to pemetrexed occurring in ≥10% of cycles included thrombocytopenia (30%), fatigue (18%), nausea (14), hyperglycemia (13%), rash (11%), vomiting (13%), and hypophosphatemia (11%). Conclusions Pemetrexed, administered as an intravenous infusion every 21 days, was tolerable in children and adolescents with refractory solid tumors, including CNS tumors, but did not show evidence of objective anti-tumor activity in the childhood tumors studied.

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5,10-Methenyltetrahydrofolate synthetase activity is increased in tumors and modifies the efficacy of antipurine LY309887

Cited by 14 publications

References 24 publications

Dynamic Regulation of a Metabolic Multi-enzyme Complex by Protein Kinase CK2

Dynamic Regulation of a Metabolic Multi-enzyme Complex by Protein Kinase CK2

Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria

Phase 2 trial of pemetrexed in children and adolescents with refractory solid tumors: A Children's Oncology Group study

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