Msh2 Deficiency Attenuates But Does Not Abolish Thiopurine Hematopoietic Toxicity inMsh2-/-Mice

Krynetskaia, Natalia F.; Brenner, Timothy L.; Krynetski, Eugene Y.; Du, William W.; Panetta, John C.; Pui, Ching‐Hon; Evans, William E.

doi:10.1124/mol.64.2.456

Cited by 11 publications

(16 citation statements)

References 34 publications

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“…Our results may be explained by published data that both MMRdeficient and -proficient cells are sensitive to relatively high concentrations of 6-TG (19), and that MSH2-deficient mice are still sensitive to mercaptopurine, another purine antimetabolite (20). However, we do not know the kind of DNA damage that is critical for apoptosis induced by 6-TG in CK2-reduced cells.…”

Section: Clinical Cancer Research 2361contrasting

confidence: 51%

“…However, we did find an enhanced G 2 -M arrest in the MMRproficient cells, similar to our prior data (19). These results may be related to the observation that both MMR-deficient and -proficient cells are sensitive to relatively high concentrations of 6-TG (19), and that MSH2-deficient mice are still sensitive to mercaptopurine, another purine antimetabolite used as a chemotherapeutic drug (20).…”

Section: Resultsmentioning

confidence: 92%

“…However, MMR-deficient cells, which do not show a clear G 2 -M arrest with 6-TG treatment, are also sensitive to higher doses of 6-TG (19). Additionally, although MSH2 knock-out mice were relatively resistant to 6-mercaptopurine treatment compared with wild-type mice, lethality was seen at higher 6-mercaptopurine doses (20), suggesting that these purine antimetabolites (6-TG and 6-mercaptopurine) have dose-related cytotoxicity independent of MMR.…”

Section: Introductionmentioning

confidence: 99%

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Casein Kinase 2 Regulates Both Apoptosis and the Cell Cycle Following DNA Damage Induced by 6-Thioguanine

Yamane

Kinsella²

2005

Clinical Cancer Research

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Purpose: The purine antimetabolite, 6-thioguanine (6-TG), is an effective drug in the management of acute leukemias. In this study, we analyze the mechanisms of apoptosis associated with 6-TG treatment and casein kinase 2 (CK2 or CKII) in human tumor cells. Experimental Design: Small interfering RNA and chemical CK2 inhibitors were used to reduce CK2 activity. Control and CK2 activity–reduced cells were cultured with 6-TG and assessed by flow cytometry to measure apoptosis and cell cycle profiles. Additionally, confocal microscopy was used to assess localization of CK2 catalytic units following 6-TG treatment. Results: Transfection of small interfering RNA against the CK2 α and/or α′ catalytic subunits results in marked apoptosis of HeLa cells following treatment with 6-TG. Chemical inhibitors of CK2 also induce apoptosis following 6-TG treatment. Apoptosis induced by 6-TG is similarly observed in both mismatch repair-proficient and -deficient HCT116 and HeLa cells. Concomitant treatment with a pan-caspase inhibitor or transfection of apoptosis repressor with caspase recruitment domain markedly suppresses the apoptotic response to DNA damage by 6-TG in the CK2-reduced cells, indicating caspase regulation by CK2. CK2 α relocalizes to the endoplasmic reticulum after 6-TG treatment. Additionally, transfection of Cdc2 with a mutation at Ser39 to Ala, which is the CK2 phosphorylation site, partially inhibits cell cycle progression in G1 to G2 phase following 6-TG treatment. Conclusion: CK2 is essential for apoptosis inhibition following DNA damage induced by 6-TG, controlling caspase activity.

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Section: Clinical Cancer Research 2361contrasting

confidence: 51%

Section: Resultsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Casein Kinase 2 Regulates Both Apoptosis and the Cell Cycle Following DNA Damage Induced by 6-Thioguanine

Yamane

Kinsella²

2005

Clinical Cancer Research

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“…TGTP is further reduced to deoxy-thioguanosine triphosphate (TdGTP) that is incorporated into double strand DNA (DNA-TG) to trigger futile mismatch repair and eventually apoptosis 1,24–28 . The integration of thioguanine into DNA is widely accepted as one of the principal sites of action for thiopurine drugs and a major process responsible for their cytotoxic effects 8,27–31 .…”

Section: Introductionmentioning

confidence: 99%

NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity

et al. 2016

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Widely used as anti-cancer and immunosuppressive agents, thiopurines have narrow therapeutic indices due to frequent toxicities, partly explained by TPMT genetic polymorphisms. Recent studies identified germline NUDT15 variation as another critical determinant of thiopurine intolerance, but the underlying molecular mechanisms and its clinical implications remain unknown. In 270 children enrolled in clinical trials for acute lymphoblastic leukemia in Guatemala, Singapore, and Japan, we identified 4 NUDT15 coding variants (p.Arg139Cys, p.Arg139His, p.Val18Ile, p.Val18_Val19insGlyVal) that resulted in 74.4%–100% loss of nucleotide diphosphatase activity. Loss-of-function NUDT15 diplotypes were consistently associated with thiopurine intolerance across three cohorts (P=0.021, 2.1×10−5, and 0.0054, respectively; meta-analysis P=4.45×10−8, allelic effect size=−11.5). Mechanistically, NUDT15 inactivated thiopurine metabolites and decreased its cytotoxicity in vitro, and patients with defective NUDT15 alleles showed excessive thiopurine active metabolites and toxicity. Taken together, our results indicate that a comprehensive pharmacogenetic model integrating NUDT15 variants may inform personalized thiopurine therapy.

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“…Uridine (1 g/kg in 100 l of 0.9% NaCl [11]) or an equal volume of saline was administered to conscious mice by intraperitoneal injection every 12 h for 8 d before infection, and then throughout the infection period. 6-MP (35 mg/kg in 100 l of 1 N NaOH, adjusted to pH 7.9 with 2 M Na 2 HPO 4 [12]) was administered by intraperitoneal injection every 24 h, for 5 d before infection, and then throughout the infection period. All chemicals were from Sigma (St. Louis, MO).…”

Section: Systemic Inhibition Of De Novo Pyrimidine and Purine Synthesismentioning

confidence: 99%

Leflunomide Prevents Alveolar Fluid Clearance Inhibition by Respiratory Syncytial Virus

Davis

Lazarowski

Hickman-Davis

et al. 2006

Am J Respir Crit Care Med

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Rationale: Previously, we demonstrated that intranasal infection of BALB/c mice with respiratory syncytial virus (RSV) resulted in an early 40% reduction in alveolar fluid clearance (AFC), an effect mediated via P2Y purinergic receptors. Objectives: To confirm that RSV-induced inhibition of AFC is mediated by uridine triphosphate (UTP), and to demonstrate that inhibition of de novo pyrimidine synthesis with leflunomide prevents increased UTP release after RSV infection, and thereby also prevents inhibition of AFC by RSV. Methods: BALB/c mice were infected intranasally with RSV strain A2. AFC was measured in anesthetized, ventilated mice by instillation of 5% bovine serum albumin into the dependent lung. Some mice were pretreated with leflunomide or 6-mercaptopurine. Measurements and Main Results: RSV-mediated inhibition of AFC is associated temporally with a 20-nM increase in UTP and ATP content of bronchoalveolar lavage fluid, hypoxemia, and altered nasal potential difference. RSV-mediated nucleotide release, AFC inhibition, and physiologic sequelae thereof can be prevented by pretreatment of mice with the de novo pyrimidine synthesis inhibitor leflunomide, which is not toxic to the mice, and which does not affect RSV replication in the lungs. In contrast, pretreatment of mice with 6-mercaptopurine, an inhibitor of de novo purine synthesis, has no beneficial effect on AFC or other indicators of disease progression. Finally, RSV-mediated inhibition of AFC is prevented by volumeregulated anion channel inhibitors. Conclusion: Pyrimidine synthesis or release pathways may provide novel therapeutic targets to counter the pathophysiologic sequelae of impaired AFC in RSV disease.Keywords: ion transport; paramyxovirus infections; pneumonia, viral; pulmonary edemaThe dominant ion transport process of the alveolar epithelium is active movement of Na ϩ ions from the airspace lining fluid to the interstitium (1). This creates an osmotic gradient, causing water to follow passively. This process of alveolar fluid clearance (AFC) is crucial to efficient gas exchange. Importantly, patients with acute lung injury with intact AFC have lower morbidity and mortality than those with compromised AFC (2).Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract disease in infants and children worldwide (3), but its pathogenesis remains poorly understood. Previously, we demonstrated that infection of BALB/c mice with RSV results in reduced AFC at early time points after infection, and inferred that RSV-mediated inhibition of AFC 2 d after infection was mediated by uridine triphosphate (UTP), acting on P2Y receptors (P2YRs) on lung epithelial cells (4). The aim of the current study was to confirm the central role of UTP in mediating the inhibitory effects of RSV on AFC, and to demonstrate that pharmacologic inhibition of de novo pyrimidine synthesis with leflunomide prevents increased UTP release after RSV infection, and thereby also prevents inhibition of AFC by RSV. Furthermore, we demonstrated that blockag...

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Msh2 Deficiency Attenuates But Does Not Abolish Thiopurine Hematopoietic Toxicity inMsh2^-/-Mice

Cited by 11 publications

References 34 publications

Casein Kinase 2 Regulates Both Apoptosis and the Cell Cycle Following DNA Damage Induced by 6-Thioguanine

Casein Kinase 2 Regulates Both Apoptosis and the Cell Cycle Following DNA Damage Induced by 6-Thioguanine

NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity

Leflunomide Prevents Alveolar Fluid Clearance Inhibition by Respiratory Syncytial Virus

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