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https://www.readbyqxmd.com/read/29342136/clonal-evolution-mechanisms-in-nt5c2-mutant-relapsed-acute-lymphoblastic-leukaemia
#1
Gannie Tzoneva, Chelsea L Dieck, Koichi Oshima, Alberto Ambesi-Impiombato, Marta Sánchez-Martín, Chioma J Madubata, Hossein Khiabanian, Jiangyan Yu, Esme Waanders, Ilaria Iacobucci, Maria Luisa Sulis, Motohiro Kato, Katsuyoshi Koh, Maddalena Paganin, Giuseppe Basso, Julie M Gastier-Foster, Mignon L Loh, Renate Kirschner-Schwabe, Charles G Mullighan, Raul Rabadan, Adolfo A Ferrando
Relapsed acute lymphoblastic leukaemia (ALL) is associated with resistance to chemotherapy and poor prognosis. Gain-of-function mutations in the 5'-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine and are selectively present in relapsed ALL. Yet, the mechanisms involved in NT5C2 mutation-driven clonal evolution during the initiation of leukaemia, disease progression and relapse remain unknown. Here we use a conditional-and-inducible leukaemia model to demonstrate that expression of NT5C2(R367Q), a highly prevalent relapsed-ALL NT5C2 mutation, induces resistance to chemotherapy with 6-mercaptopurine at the cost of impaired leukaemia cell growth and leukaemia-initiating cell activity...
January 17, 2018: Nature
https://www.readbyqxmd.com/read/29338679/therapeutic-role-of-methotrexate-in-pediatric-crohn-s-disease
#2
REVIEW
Zlatko Djurić, Ljiljana Šaranac, Ivana Budić, Voja Pavlović, Jelena Djordjević
The main role of therapy in Crohn's disease is to achieve long-term clinical remission, and to allow for normal growth and development of children. The immunomodulatory drugs used for the maintenance of remission in Crohn's disease include thiopurines (azathioprine and 6-mercaptopurine) and methotrexate. Development of hepatosplenic T-cell lymphoma in some patients with inflammatory bowel disease, treated with thiopurines independently or in combination with anti-tumor necrosis factor agents, resulted in a growing interest in the therapeutic application of methotrexate in children suffering from Crohn's disease...
January 16, 2018: Bosnian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/29315147/nonmelanoma-skin-cancer-risk-in-patients-with-inflammatory-bowel-disease-undergoing-thiopurine-therapy-a-systematic-review-of-the-literature
#3
Joshua W Hagen, Melissa A Pugliano-Mauro
BACKGROUND: Azathioprine and 6-mercaptopurine (thiopurines) are common adjunct treatments for inflammatory bowel disease (IBD). Although thiopurine therapy in organ transplant recipients is known to increase nonmelanoma skin cancers (NMSCs), dermatologic literature yields less data regarding NMSC risk of thiopurine use in IBD. OBJECTIVE: The aim of this study was to systematically review current literature on NMSC risk in patients with IBD using thiopurine therapy...
January 8, 2018: Dermatologic Surgery: Official Publication for American Society for Dermatologic Surgery [et Al.]
https://www.readbyqxmd.com/read/29288282/promotion-of-sh-sy5y-cell-growth-by-gold-nanoparticles-modified-with-6-mercaptopurine-and-a-neuron-penetrating-peptide
#4
Yaruo Xiao, Enqi Zhang, Ailing Fu
Much effort has been devoted to the discovery of effective biomaterials for nerve regeneration. Here, we reported a novel application of gold nanoparticles (AuNPs) modified with 6-mercaptopurine (6MP) and a neuron-penetrating peptide (RDP) as a neurophic agent to promote proliferation and neurite growth of human neuroblastoma (SH-SY5Y) cells. When the cells were treated with 6MP-AuNPs-RDP conjugates, they showed higher metabolic activity than the control. Moreover, SH-SY5Y cells were transplanted onto the surface coated with 6MP-AuNPs-RDP to examine the effect of neurite development...
December 29, 2017: Nanoscale Research Letters
https://www.readbyqxmd.com/read/29285220/dietary-polyphenols-influence-antimetabolite-agents-methotrexate-6-mercaptopurine-and-5-fluorouracil-in-leukemia-cell-lines
#5
Amani Mahbub, Christine Le Maitre, Sarah Haywood-Small, Neil Cross, Nicola Jordan-Mahy
Polyphenols have been previously shown to sensitize leukemia cell lines to topoisomerase inhibitors. Here, we assess the effects of five polyphenols when used alone and in combination with antimetabolites: methotrexate, 6-mercaptopurine and 5-fluorouracil; in lymphoid and myeloid leukemia cells lines, and non-tumor control cells. The effects of combined treatments were investigated on ATP and glutathione levels, cell-cycle progression, DNA damage and apoptosis. Polyphenols antagonized methotrexate and 6-mercaptopurine induced cell-cycle arrest and apoptosis in most leukemia cell lines...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29282389/listeria-monocytogenes-brain-abscess-in-crohn-s-disease-treated-with-adalimumab
#6
Amporn Atsawarungruangkit, Fernando Dominguez, Gustavo Borda, Nikolaos Mavrogiorgos
Listeria monocytogenes is a gram-positive bacterium that causes listeriosis. Brain abscess is a very uncommon manifestation of listeriosis and has not been reported to be associated with adalimumab (humira), one of the approved medications for treating Crohn's disease. A 45-year-old female with Crohn's disease presented with sudden onset of fever, headache, nausea, vomiting, and altered mental status for 1 day. She was on prednisone and 6-mercaptopurine. She had started taking adalimumab 17 days prior to admission...
September 2017: Case Reports in Gastroenterology
https://www.readbyqxmd.com/read/29197275/a-sensitive-turn-on-fluorescent-probe-for-detection-of-biothiols-using-mno2-carbon-dots-nanocomposites
#7
Dimple Garg, Akansha Mehta, Amit Mishra, Soumen Basu
Presently, the combination of carbon quantum dots (CQDs) and metal oxide nanostructures in one frame are being considered for the sensing of purine compounds. In this work, a combined system of CQDs and MnO2 nanostructures was used for the detection of anticancer drugs, 6-Thioguanine (6-TG) and 6-Mercaptopurine (6-MP). The CQDs were synthesized through microwave synthesizer and the MnO2 nanostructures (nanoflowers and nanosheets) were synthesized using facile hydrothermal technique. The CQDs exhibited excellent fluorescence emission at 420nm when excited at 320nm wavelength...
November 21, 2017: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
https://www.readbyqxmd.com/read/29197117/addition-of-allopurinol-for-altering-thiopurine-metabolism-to-optimize-therapy-in-patients-with-inflammatory-bowel-disease
#8
Geoffrey C Wall, Hamid Muktar, Cassandra Effken, Pramod B Mahajan
Thiopurine drugs, including azathioprine and 6-mercaptopurine, are used commonly in patients with inflammatory bowel disease for maintenance of remission. Although generally well tolerated, adverse effects lead to discontinuation in a significant minority of patients. Pharmacogenomic studies have suggested that metabolic breakdown of azathioprine in an individual is genetically determined. Coupled with the fact that certain thiopurine metabolites, notably 6-thioguanine nucleotide and 6-methylmercaptopurine, are associated with antiinflammatory effects and adverse effects, respectively, some investigators have examined intentionally shunting the metabolism of azathioprine toward increasing 6-thioguanine nucleotide levels by using low doses of the xanthine oxidoreductase inhibitor allopurinol to improve efficacy and decrease toxicity of azathioprine in patients with inflammatory bowel disease...
December 1, 2017: Pharmacotherapy
https://www.readbyqxmd.com/read/29194039/validation-of-a-high-performance-liquid-chromatography-method-for-thiopurine-s-methyltransferase-activity-in-whole-blood-using-6-mercaptopurine-as-substrate
#9
Hannah Rieger, Patrik Schmidt, Elke Schaeffeler, Manabu Abe, Mira Schiffhauer, Matthias Schwab, Nicolas von Ahsen, Gabriela Zurek, Hartmut Kirchherr, Maria Shipkova, Eberhard Wieland
BACKGROUND: Variation in metabolism, toxicity and therapeutic efficacy of thiopurine drugs is largely influenced by genetic polymorphisms in the thiopurine S-methyltransferase (TPMT) gene. Determination of TPMT activity is routinely performed in patients to adjust drug therapy. METHODS: We further optimized a previously established high-performance liquid chromatography (HPLC) method by measuring TPMT activity in whole blood instead of isolated erythrocytes, which is based on conversion of 6-mercaptopurine to 6-methylmercaptopurine using S-adenosyl-methionine as methyl donor...
December 1, 2017: Clinical Chemistry and Laboratory Medicine: CCLM
https://www.readbyqxmd.com/read/29192347/pharmacogenetics-of-thiopurines-for-inflammatory-bowel-disease-in-east-asia-prospects-for-clinical-application-of-nudt15-genotyping
#10
REVIEW
Yoichi Kakuta, Yoshitaka Kinouchi, Tooru Shimosegawa
The thiopurine drugs 6-mercaptopurine (6-MP) and azathiopurine (AZA) are widely used to treat inflammatory bowel disease. However, the incidence of adverse reactions is high, particularly in Asia, and the mechanisms of toxicity in Asian populations remain unclear. Thiopurine S-methyltransferase (TPMT) is a well-known enzyme that inactivates AZA or 6-MP through methylation and is one of the few pharmacogenetic predictors used in clinical settings in Western countries. Individuals carrying TPMT-deficient genetic variants require reduced drug doses, but this treatment modification is are not applicable to East Asian populations...
November 30, 2017: Journal of Gastroenterology
https://www.readbyqxmd.com/read/29188741/adherence-to-oral-medications-during-maintenance-therapy-among-children-and-adolescents-with-acute-lymphoblastic-leukemia-a-medication-refill-analysis
#11
Yelena P Wu, David D Stenehjem, Lauri A Linder, Bin Yu, Bridget Grahmann Parsons, Ryan Mooney, Mark N Fluchel
Adherence to oral medications during maintenance therapy is essential for pediatric patients with acute lymphoblastic leukemia. Self-reported or electronic monitoring of adherence indicate suboptimal adherence, particularly among particular sociodemographic groups. This study used medication refill records to examine adherence among a national sample of pediatric patients with acute lymphoblastic leukemia. Patients in a national claims database, aged 0 to 21 years with a diagnosis of acute lymphoblastic leukemia and in the maintenance phase of treatment, were included...
November 1, 2017: Journal of Pediatric Oncology Nursing: Official Journal of the Association of Pediatric Oncology Nurses
https://www.readbyqxmd.com/read/29175587/design-synthesis-and-molecular-modeling-studies-of-new-series-of-antitumor-1-2-4-triazines-with-potential-c-met-kinase-inhibitory-activity
#12
Marwa H El-Wakil, Hayam M Ashour, Manal N Saudi, Ahmed M Hassan, Ibrahim M Labouta
The receptor tyrosine kinase c-Met is an attractive target for therapeutic treatment of cancers nowadays. Herein we describe the design and synthesis of a novel series of 1,2,4-triazine derivatives based on our lead NCI 748494/1, possessing different N-linkers to aromatic and heterocyclic rings. In addition, a molecular hybrid series combining the 1,2,4-triazine scaffold to the well-known anticancer drug 6-mercaptopurine (6-MP) was synthesized in order to explore its "double-drug" antitumor effect. The synthesized compounds were evaluated for their in vitro antitumor activity against three c-Met addicted cancer cell lines (A549, HT-29 and MKN-45)...
November 16, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29147133/allopurinol-in-combination-with-thiopurine-induces-mucosal-healing-and-improves-clinical-and-metabolic-outcomes-in-ibd
#13
Brigitte Moreau, Pierre Clement, Yves Theoret, Ernest G Seidman
Background: Thiopurines, azathioprine (AZA) and 6-mercaptopurine (6-MP) are common maintenance medications for inflammatory bowel disease (IBD). Excessive methylation via thiopurine methyltransferase (TPMT) frequently causes therapeutic failure. Allopurinol reduces excessive 6-methyl-mercaptopurine (6-MMP) while enhancing 6-thioguanine (6-TGN) levels. The aim of this study was to evaluate clinical, metabolic and endoscopic impact of allopurinol in combination with low-dose thiopurine in IBD...
November 2017: Therapeutic Advances in Gastroenterology
https://www.readbyqxmd.com/read/29142523/steroid-refractory-extensive-enteritis-complicated-by-ulcerative-colitis-successfully-treated-with-adalimumab
#14
Shinji Okabayashi, Taku Kobayashi, Tomohisa Sujino, Ryo Ozaki, Satoko Umeda, Takahiko Toyonaga, Eiko Saito, Masaru Nakano, Maria Carla Tablante, Shojiroh Morinaga, Toshifumi Hibi
Extracolonic involvement of the gastrointestinal tract is extremely uncommon in ulcerative colitis (UC) and rarely found in the upper gastrointestinal tract or in postoperative cases since it typically responds to steroids. Here we report a case of UC complicated by extensive ileal inflammation that was refractory to steroids. A 20-year-old man was diagnosed with UC of typical pancolitis without ileal involvement and started treatment with pH-dependent mesalazine and oral prednisolone. Although his symptoms transiently resolved, the condition flared when the steroid dose was tapered down...
October 2017: Intestinal Research
https://www.readbyqxmd.com/read/29140288/capillary-electrophoresis-hyphenated-with-mass-spectrometry-for-determination-of-inflammatory-bowel-disease-drugs-in-clinical-urine-samples
#15
Katarína Maráková, Juraj Piešťanský, Zuzana Zelinková, Peter Mikuš
Azathioprine is the main thiopurine drug used in the treatment of immune-based inflammations of gastrointestinal tract. For the purpose of therapy control and optimization, effective and reliable analytical methods for a rapid drug monitoring in biological fluids are essential. Here, we developed a separation method based on the capillary electrophoresis (CE) hyphenated with tandem mass spectrometry (MS/MS) for the simultaneous determination of azathioprine and its selected metabolites (6-thioguanine, 6-mercaptopurine, and 6-methylmercaptopurine) as well as other co-medicated drugs (mesalazine, prednisone, and allopurinol)...
November 15, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29081195/-impact-of-intensified-maintenance-therapy-on-the-prognosis-of-children-and-adolescents-with-advanced-lymphoblastic-lymphoma
#16
K B Yang, X F Sun, Z Z Zhen, S Y Lu, J Zhu, F F Sun, J Wang, J T Huang, R R Chen, L T Ye, Y Liu, Z Y You
Objective: To investigate the impact of intensified maintenance therapy on the prognosis of children and adolescents with advanced lymphoblastic lymphoma (LBL) . Methods: Retrospective analysis on the treatment results of children and adolescents with stage Ⅲ and stage Ⅳ LBL who underwent BFM-NHL-90/-95 regimen without prophylactic radiotherapy. The intensified therapy group included the patients admitted from 1998 to 2005, while others were classified as the non-intensified therapy group. Patients in the intensified therapy group were intravenously treated with "etoposide phosphate plus cytrarabine" and high-dose methotrexate alternately per 2...
September 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/29052026/high-dose-chemotherapy-and-autologous-peripheral-blood-stem-cell-transplantation-with-bcvac-regimen-followed-by-maintenance-chemotherapy-for-children-with-very-high-risk-acute-lymphoblastic-leukemia
#17
Che Ry Hong, Hyoung Jin Kang, Kyung Duk Park, Hee Young Shin, Hyo Seop Ahn
Allogeneic hematopoietic stem cell transplantation (HSCT) is the recommended treatment for children with very high risk acute lymphoblastic leukemia (ALL), but it requires adequate institutional infrastructure, experience, and expertise, especially for alternative donor HSCT. We review our experience with high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (APBSCT), followed by post-APBSCT maintenance chemotherapy for children with very high risk ALL. Between August 1997 and November 2012, our institute was not successful with HLA-haploidentical HSCT...
October 20, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28983968/individualized-6-mercaptopurine-increments-in-consolidation-treatment-of-childhood-acute-lymphoblastic-leukemia-a-nopho-randomized-controlled-trial
#18
Morten Tulstrup, Thomas L Frandsen, Jonas Abrahamsson, Bendik Lund, Kim Vettenranta, Olafur Gisli Jonsson, Hanne Vibeke Hansen Marquart, Birgitte Klug Albertsen, Mats Heyman, Kjeld Schmiegelow
OBJECTIVES: This randomized controlled trial tested the hypothesis that children with non-high risk acute lymphoblastic leukemia could benefit from individualized 6-mercaptopurine increments during consolidation therapy (NCT00816049). Primary and secondary end points were end of consolidation minimal residual disease (MRD) positivity and event-free survival. METHODS: 392 patients were randomized to experimental and 396 to standard therapy. Patients allocated to standard therapy received oral 6-mercaptopurine (25 mg/m(2) /day) from days 30 to 85, while the experimental arm received stepwise increments of additional 25 mg/m(2) /day beginning on days 50 and/or 71 unless dose-limiting myelosuppression had occurred...
October 6, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28966507/thiopurine-s-methyltransferase-polymorphisms-in-korean-dermatologic-patients
#19
Minseok Lee, Jimyung Seo, Dongsik Bang, Do Young Kim
BACKGROUND: Thiopurine S-methyltransferase (TPMT) is an important enzyme in the metabolism of thiopurines including azathioprine (AZA), 6-mercaptopurine, and 6-thioguanine. TPMT genotyping is widely used for screening of AZA-related toxicity during routine clinical practice in Korea. However, the data of TPMT genotypes and its AZA-related toxicity have not been studied in the field of dermatology. OBJECTIVE: The aim of this study was to evaluate the genetic basis of TPMT polymorphism in Korean dermatologic patients and subsequently to investigate the relationship between mutant TPMT and adverse responses to AZA treatment...
October 2017: Annals of Dermatology
https://www.readbyqxmd.com/read/28963908/emerging-role-of-nudt15-polymorphisms-in-6-mercaptopurine-metabolism-and-dose-related-toxicity-in-acute-lymphoblastic-leukaemia
#20
REVIEW
Minu Singh, Prateek Bhatia, Sanjeev Khera, Amita Trehan
Despite more than 80% long term survival in ALL, morbidity due to drug related myelotoxicity remains high. Germline variants of thiopurine metabolizing enzymes (TPMT and ITPA) have been described which are associated with increased drug toxicity during maintenance phase, but their prevalence in different ethnic groups is variable to account for relatively high myelotoxicity incidence. NUDT15 variant (rs116855232) has been recently identified as a novel polymorphism related with thiopurine-induced leucopenia in inflammatory bowel disease and ALL...
November 2017: Leukemia Research
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