EFA (9-β-D-erythrofuranosyladenine) is an effective salvage agent for methylthioadenosine phosphorylase-selective therapy of T-cell acute lymphoblastic leukemia with L-alanosine

Batova, Ayse; Cottam, Howard B.; Yu, John; Diccianni, Mitchell B.; Carrera, Carlos J.; Yu, Alice L.

doi:10.1182/blood-2005-06-2430

Cited by 30 publications

(39 citation statements)

References 29 publications

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“…The chemicals MTA, 3-Deaza and adenosine, were purchased from SigmaAldrich, Aza-CdR was obtained from Biomol/Cayman. The HLA-A2-binding peptide Melan-A [26][27][28][29][30][31][32][33][34][35] (ELAGIGILTV) was prepared by Bachem. Soluble recombinant HCMV pp65 (low endotoxin) was obtained from Miltenyi Biotec.…”

Section: Media Chemicals Cytokines Peptides and Generation Of Denmentioning

confidence: 99%

“…78 Briefly, CD8 C T cells were magnetically enriched (Miltenyi Biotec) from peripheral blood mononuclear cells (PBMC) of healthy donors and restimulated weekly with Mart-1 [26][27][28][29][30][31][32][33][34][35] peptide-pulsed moDCs (generated as described above) in medium containing 100 U/mL IL-2 (Proleukin). Mart-1-specific T cells were determined by Mart-1-MHC tetramer staining (Beckman Coulter).…”

Section: Generation Of Antigen-specific Cd8mentioning

confidence: 99%

“…[25][26][27] The effect of MTA on tumor cells remains controversial: while intracellular concentrations of 0.5-5 mM MTA seem to promote tumor progression, [26][27][28] higher concentrations of MTA interfere with cell proliferation, tumor development, invasiveness and regulation of apoptosis, 29,30 MTA has been shown to be toxic to hematopoietic progenitor cells in vitro with an IC 50 equal or less than 1 mM. 31 In contrast, MTA has been tested in mice and rats and found to be non-toxic at high doses even when given over extended periods. 30,32 One further potent biochemical mechanism of MTA is its inhibition of methylation.…”

Section: Introductionmentioning

confidence: 99%

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Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

et al. 2016

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The immunosuppressive tumor microenvironment represents one of the main obstacles for immunotherapy of cancer. The tumor milieu is among others shaped by tumor metabolites such as 5 0 -deoxy-5 0 -methylthioadenosine (MTA). Increased intratumoral MTA levels result from a lack of the MTAcatabolizing enzyme methylthioadenosine phosphorylase (MTAP) in tumor cells and are found in various tumor entities. Here, we demonstrate that MTA suppresses proliferation, activation, differentiation, and effector function of antigen-specific T cells without eliciting cell death. Conversely, if MTA is added to highly activated T cells, MTA exerts cytotoxic effects on T cells. We identified the Akt pathway, a critical signal pathway for T cell activation, as a target of MTA, while, for example, p38 remained unaffected. Next, we provide evidence that MTA exerts its immunosuppressive effects by interfering with protein methylation in T cells. To confirm the relevance of the suppressive effects of exogenously added MTA on human T cells, we used an MTAP-deficient tumor cell-line that was stably transfected with the MTAPcoding sequence. We observed that T cells stimulated with MTAP-transfected tumor cells revealed a higher proliferative capacity compared to T cells stimulated with Mock-transfected cells. In conclusion, our findings reveal a novel immune evasion strategy of human tumor cells that could be of interest for therapeutic targeting.

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Section: Media Chemicals Cytokines Peptides and Generation Of Denmentioning

confidence: 99%

Section: Generation Of Antigen-specific Cd8mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

et al. 2016

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“…This deletion has been exploited in an attempt to develop targeted chemotherapy regimens mainly focusing on using L-alanosine, an inhibitor of adenylosuccinate dehydrogenase, a component of the de novo purine synthesis pathway. Indeed MTAP-negative cells have been shown to be far more sensitive to L-alanosine than cells replete with the enzyme (6,8,9,11), and this has led to clinical trials evaluating the use of L-alanosine in MTAPdeficient cancers (27). There is an ongoing phase II trial evaluating the activity of pemetrexed in chondrosarcomas which will correlate response with MTAP deletions that have been found in 50% of samples tested thus far (28).…”

Section: Discussionmentioning

confidence: 99%

The effect of a novel transition state inhibitor of methylthioadenosine phosphorylase on pemetrexed activity

Chattopadhyay¹,

Zhao²,

Tsai³

et al. 2006

Molecular Cancer Therapeutics

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Pemetrexed is a new-generation antifolate inhibitor of thymidylate synthase (TS) and a weaker inhibitor of glycinamide ribonucleotide transformylase (GARFT) required for de novo purine synthesis. Methylthioadenosine phosphorylase (MTAP) salvages purines by releasing adenine from methylthioadenosine and is often deleted in mesothelioma. The current study addresses the effect of MTAP on pemetrexed activity using a highly potent transition state inhibitor of MTAP, MT-DADMe-Immucillin A (ImmA; K i = 86 pmol/L) in the MTAP(+) NCI-H28 and MTAP(À) NCI-H2052 mesothelioma cell lines. Based on selective nucleoside protection, TS was found to be the primary pemetrexed target in both cell lines with GARFT inhibition requiring 20-to 30-fold higher pemetrexed concentrations. ImmA had no effect on pemetrexed activity but, when thymidine was added, the pemetrexed IC 50 decreased by a factor of f3 in MTAP(+) H28 cells with no effect in MTAP(À) H2052 cells. Conversely, the transfection of MTAP into H2052 cells increased the pemetrexed IC 50 by nearly 3-fold but only in the presence of thymidine; this was reversed by ImmA. An MTAPspecific short interfering RNA produced a 2-fold decrease in pemetrexed IC 50 in MTAP(+) HeLa cells in the presence of thymidine. These data indicate that suppression of constitutive MTAP has no effect on pemetrexed activity when the primary target is TS. There is a modest salutary effect when the pemetrexed target is GARFT alone. [Mol Cancer Ther 2006;5(10):2549 -55]

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“…Hadacidin (N-formyl-N-hydroxyglycine) is an analog of L-aspartate, but inhibits only adenylosuccinate synthetase (1)(2)(3)19,20). Many cancers (30% of all T-cell acute lymphocytic leukemia, for instance) lack a salvage pathway for adenine nucleotides and rely entirely on de novo biosynthesis of purine nucleotides (21). Inhibition of adenylosuccinate synthetase in such tumors would directly decrease the pool of adenine nucleotides, whereas normal cells with intact salvage mechanisms would be impacted to a lesser extent.…”

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confidence: 99%

Cavitation as a Mechanism of Substrate Discrimination by Adenylosuccinate Synthetases^,

et al. 2006

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Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, coupling L-aspartate and IMP to form adenylosuccinate. K m values of IMP and 2′-deoxy-IMP are nearly identical with each substrate supporting comparable maximal velocities. Nonetheless, the K m value for L-aspartate and the K i value for hadacidin (a competitive inhibitor with respect to L-aspartate) are 29-to 57-fold lower in the presence of IMP than 2′-deoxy-IMP. Crystal structures of the synthetase ligated with hadacidin, GDP and either 6-phosphoryl-IMP or 2′-deoxy-6-phosphoryl-IMP are identical except for the presence of a cavity normally occupied by the 2′-hydroxyl group of IMP. In the presence of 6-phosphoryl-IMP and GDP (hadacidin absent), the L-aspartate pocket can retain its fully ligated conformation, forming hydrogen bonds between the 2′-hydroxyl group of IMP and sequence-invariant residues. In the presence of 2′-deoxy-6-phosphoryl-IMP and GDP, however, the L-aspartate pocket is poorly ordered. The absence of the 2′-hydroxyl group of the deoxy-ribonucleotide may destabilize ligand binding to the L-aspartate pocket by disrupting hydrogen bonds that maintain a favorable protein conformation and by the introduction of a cavity in the fully ligated active site. At an approximate energy cost of 2.2 kcal/ mol, the unfavorable thermodynamics of cavity formation may be the major factor in destabilizing ligands at the L-aspartate pocket. Graphical Abstract

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EFA (9-β-D-erythrofuranosyladenine) is an effective salvage agent for methylthioadenosine phosphorylase-selective therapy of T-cell acute lymphoblastic leukemia with L-alanosine

Cited by 30 publications

References 29 publications

Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

The effect of a novel transition state inhibitor of methylthioadenosine phosphorylase on pemetrexed activity

Cavitation as a Mechanism of Substrate Discrimination by Adenylosuccinate Synthetases^,

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EFA (9-β-D-erythrofuranosyladenine) is an effective salvage agent for methylthioadenosine phosphorylase-selective therapy of T-cell acute lymphoblastic leukemia with L-alanosine

Cited by 30 publications

References 29 publications

Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

The effect of a novel transition state inhibitor of methylthioadenosine phosphorylase on pemetrexed activity

Cavitation as a Mechanism of Substrate Discrimination by Adenylosuccinate Synthetases,

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Cavitation as a Mechanism of Substrate Discrimination by Adenylosuccinate Synthetases^,