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https://www.readbyqxmd.com/read/28070705/enzymatic-activation-of-double-targeted-5-o-l-valyl-decitabine-prodrug-by-biphenyl-hydrolase-like-protein-and-its-molecular-design-basis
#1
Wenhui Tao, Dongyang Zhao, Mengchi Sun, Meng Li, Xiangyu Zhang, Zhonggui He, Yinghua Sun, Jin Sun
A primary focus of this research was to explore the activation process and mechanism of decitabine (5-aza-2'-deoxycytidine, DAC) prodrug. Recently, it has been reported that biphenyl hydrolase-like protein (BPHL) can play an important role in the activation of some amino acid nucleoside prodrugs with a general preference for hydrophobic amino acids and 5'-esters. Therefore, we put forward a bold hypothesis that this novel enzyme may be primarily responsible for the activation process of DAC prodrug as well...
January 9, 2017: Drug Delivery and Translational Research
https://www.readbyqxmd.com/read/28058491/evaluating-the-impact-of-genetic-and-epigenetic-aberrations-on-survival-and-response-in-acute-myeloid-leukemia-patients-receiving-epigenetic-therapy
#2
Jan K Hiller, Claudia Schmoor, Verena I Gaidzik, Charlotte Schmidt-Salzmann, Arzu Yalcin, Mahmoud Abdelkarim, Nadja Blagitko-Dorfs, Konstanze Döhner, Lars Bullinger, Justus Duyster, Michael Lübbert, Björn Hackanson
Treatment with hypomethylating agents such as decitabine, which results in overall response rates of up to 50%, has become standard of care in older patients with acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy. However, there still exists a lack of prognostic and predictive molecular biomarkers that enable selection of patients who are likely to benefit from epigenetic therapy. Here, we investigated distinct genetic (FLT3-ITD, NPM1, DNMT3A) and epigenetic (estrogen receptor alpha (ERα), C/EBPα, and OLIG2) aberrations in 87 AML patients from the recently published phase II decitabine trial (AML00331) to identify potential biomarkers for patients receiving hypomethylating therapy...
January 5, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/28058097/genetics-and-epigenetics-of-myelodysplastic-syndromes-and-response-to-drug-therapy-new-insights
#3
REVIEW
Saeid Shahrabi, Abbas Khosravi, Mohammad Shahjahani, Fakher Rahim, Najmaldin Saki
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic neoplasms ocurring mostly in the elderly. The clinical outcome of MDS patients is still poor despite progress in treatment approaches. About 90% of patients harbor at least one somatic mutation. This review aimed to assess the potential of molecular abnormalities in understanding pathogenesis, prognosis, diagnosis and in guiding choice of proper therapy in MDS patients. Papers related to this topic from 2000 to 2016 in PubMed and Scopus databases were searched and studied...
October 10, 2016: Oncology Reviews
https://www.readbyqxmd.com/read/28052028/establishment-and-characterization-of-hypomethylating-agent-resistant-cell-lines-molm-aza-1-and-molm-dec-5
#4
Eun-Hye Hur, Seung-Hyun Jung, Bon-Kwan Goo, Juhyun Moon, Yunsuk Choi, Dae Ro Choi, Yeun-Jun Chung, Je-Hwan Lee
Two hypomethylating agents (HMAs), azacitidine and decitabine, have demonstrated clinical activities in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML); however, potential problems include development of acquired resistance. HMA-resistant patients have very poor prognosis and this cohort of patients constitutes an important area of research. To understand the mechanisms underlying HMA-resistance and to overcome it, we established an azacitidine-resistant cell line, MOLM/AZA-1 and a decitabine-resistant cell line, MOLM/DEC-5 using MOLM-13...
December 28, 2016: Oncotarget
https://www.readbyqxmd.com/read/28045433/functions-and-epigenetic-regulation-of-wwox-in-bone-metastasis-from-breast-carcinoma-comparison-with-primary-tumors
#5
REVIEW
Paola Maroni, Emanuela Matteucci, Paola Bendinelli, Maria Alfonsina Desiderio
Epigenetic mechanisms influence molecular patterns important for the bone-metastatic process, and here we highlight the role of WW-domain containing oxidoreductase (Wwox). The tumor-suppressor Wwox lacks in almost all cancer types; the variable expression in osteosarcomas is related to lung-metastasis formation, and exogenous Wwox destabilizes HIF-1α (subunit of Hypoxia inducible Factor-1, HIF-1) affecting aerobic glycolysis. Our recent studies show critical functions of Wwox present in 1833-osteotropic clone, in the corresponding xenograft model, and in human bone metastasis from breast carcinoma...
January 1, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28035374/activation-of-oncogenic-pathways-in-classical-hodgkin-lymphoma-by-decitabine-a-rationale-for-combination-with-small-molecular-weight-inhibitors
#6
Tatjana Maria Swerev, Thomas Wirth, Alexey Ushmorov
DNA methylation is an epigenetic control mechanism that contributes to the specific phenotype and to the oncogenic program of virtually all tumor entities. Although efficacy of demethylating agents in classical Hodgkin lymphoma (cHL) was not specifically tested, a case of regression of relapsed metastatic cHL was described as a fortunate side‑effect of the demethylating agent 5‑azacytidine in a patient with myelodysplastic syndrome. We investigated molecular mechanisms of decitabine (5‑Aza‑dC) antitumor activity in cHL using gene expression profiling followed by gene set enrichment analysis...
December 30, 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/28024498/-reactivated-expression-of-microrna-124-in-patients-with-myelodysplastic-syndromes-after-demethylating-therapy
#7
Yue-Sheng Meng, Song Gao, Fan-Li Hua, Ying Li
OBJECTIVE: To explore the role of microRNA-124(miR-124) in the pathogenesis of myelodysplastic syndromes(MDS) through detecting the expression level of miR-124 in bone marrow mononuclear cells(MNC) of MDS patients before and after demethylating therapy with decitabine. METHODS: The expression levels of miR-124 in the MNC of 35 MDS patients and 10 healthy donors were detected with stem-loop quantitative real time polymerase chain reaction assay. RESULTS: The expression level of miR-124 was lower in MDS patients than that in healthy donors...
December 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28003999/synergistic-cytotoxic-effect-of-l-asparaginase-combined-with-decitabine-as-a-demethylating-agent-in-pediatric-t-all-with-specific-epigenetic-signature
#8
Salvatore Serravalle, Salvatore N Bertuccio, Annalisa Astolfi, Fraia Melchionda, Andrea Pession
T-Acute Lymphoblastic Leukemia (T-ALL) remains a subgroup of pediatric ALL, with a lower response to standard chemotherapy. Some recent studies established the fundamental role of epigenetic aberrations such as DNA hypermethylation, to influence patients' outcome and response to chemotherapy. Moreover, L-asparaginase is an important chemotherapeutic agent for treatment of ALL and resistance to this drug has been linked to ASNS expression, which can be silenced through methylation. Therefore, we tested whether the sensitivity of T-ALL cell lines towards L-asparaginase is correlated to the epigenetic status of ASNS gene and whether the sensitivity can be modified by concurrent demethylating treatment...
2016: BioMed Research International
https://www.readbyqxmd.com/read/27995947/haematological-cancer-tp53-mutations-sensitize-to-decitabine
#9
Peter Sidaway
No abstract text is available yet for this article.
December 20, 2016: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/27995887/-a-pilot-study-of-ten-day-decitabine-regimen-as-initial-therapy-for-newly-diagnosed-elderly-patients-with-acute-myeloid-leukemia
#10
T J Qin, Z F Xu, Y Zhang, L W Fang, H L Zhang, L J Pan, N B Hu, S Q Qu, B Li, Z J Xiao
No abstract text is available yet for this article.
November 14, 2016: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/27984642/tp53-mutations-predict-decitabine-induced-complete-responses-in-patients-with-myelodysplastic-syndromes
#11
Chun-Kang Chang, You-Shan Zhao, Feng Xu, Juan Guo, Zheng Zhang, Qi He, Dong Wu, Ling-Yun Wu, Ji-Ying Su, Lu-Xi Song, Chao Xiao, Xiao Li
To identify the molecular signatures that predict responses to decitabine (DAC), we examined baseline gene mutations (28 target genes) in 109 myelodysplastic syndrome (MDS) patients at diagnosis. We determined that TP53 mutations predicted complete response (CR), as 10 of 15 patients (66·7%) who possessed TP53 mutations achieved a CR. Univariate and multivariate analyses showed that TP53 mutations are the only molecular signatures predictive of a CR to DAC in MDS. Among the ten patients with TP53 mutations who achieved a CR, nine presented with complex karyotypes due to abnormalities involving chromosome 5 and/or chromosome 7, and eight possessed monosomies...
December 16, 2016: British Journal of Haematology
https://www.readbyqxmd.com/read/27980103/repositioning-fda-approved-drugs-in-combination-with-epigenetic-drugs-to-reprogram-colon-cancer-epigenome
#12
Noël J-M Raynal, Elodie M Da Costa, Justin T Lee, Vazganush Gharibyan, Saira Ahmed, Hanghang Zhang, Takahiro Sato, Gabriel G Malouf, Jean-Pierre J Issa
Epigenetic drugs, such as DNA methylation inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi), are approved in monotherapy for cancer treatment. These drugs reprogram gene expression profiles, reactivate tumor suppressor genes (TSG) producing cancer cell differentiation and apoptosis. Epigenetic drugs have been shown to synergize with other epigenetic drugs or various anticancer drugs. To discover new molecular entities that enhance epigenetic therapy, we performed a high-throughput screening using FDA-approved libraries in combination with DNMTi or HDACi...
December 15, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27959731/tp53-and-decitabine-in-acute-myeloid-leukemia-and-myelodysplastic-syndromes
#13
John S Welch, Allegra A Petti, Christopher A Miller, Catrina C Fronick, Michelle O'Laughlin, Robert S Fulton, Richard K Wilson, Jack D Baty, Eric J Duncavage, Bevan Tandon, Yi-Shan Lee, Lukas D Wartman, Geoffrey L Uy, Armin Ghobadi, Michael H Tomasson, Iskra Pusic, Rizwan Romee, Todd A Fehniger, Keith E Stockerl-Goldstein, Ravi Vij, Stephen T Oh, Camille N Abboud, Amanda F Cashen, Mark A Schroeder, Meagan A Jacoby, Sharon E Heath, Kierstin Luber, Megan R Janke, Andrew Hantel, Niloufer Khan, Madina J Sukhanova, Randall W Knoebel, Wendy Stock, Timothy A Graubert, Matthew J Walter, Peter Westervelt, Daniel C Link, John F DiPersio, Timothy J Ley
Background The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. Methods We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients...
November 24, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27935410/establishment-of-a-high-throughput-detection-system-for-dna-demethylating-agents
#14
Eriko Okochi-Takada, Naoko Hattori, Akihiro Ito, Tohru Niwa, Mika Wakabayashi, Kana Kimura, Minoru Yoshida, Toshikazu Ushijima
Epigenetic alterations underlie various human disorders, including cancer, and this has resulted in the development of drugs targeting epigenetic alterations. Although DNA demethylating agents are one of the major epigenetic drugs, only two compounds-5-azacytidine (5-aza-CR, azacitidine) and 5-aza-2'-deoxycytidine (5-aza-dC, decitabine)-have obtained clinical approval. Here, we aimed to establish a detection system for DNA demethylating agents suitable for a high-throughput screening (HTS) in mammalian cells...
December 9, 2016: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/27905102/elevated-fetal-haemoglobin-is-a-predictor-of-better-outcome-in%C3%A2-mds-aml-patients-receiving-5-aza-2-deoxycytidine-decitabine
#15
Michael Lübbert, Gabriele Ihorst, Philipp N Sander, Ljudmila Bogatyreva, Heiko Becker, Pierre W Wijermans, Stefan Suciu, Emmanuel Bissé, Rainer Claus
Although azanucleoside DNA-hypomethylating agents (HMAs) are routinely used for the treatment of myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), very few outcome predictors have been established. Expression of the β-like globin gene locus is tightly regulated by DNA methylation, is HMA-sensitive in vitro, and fetal haemoglobin (HbF) expression is under study as a potential biomarker for response of MDS patients to azacitidine. We determined HbF expression in 16 MDS and 36 AML patients receiving decitabine (DAC)...
December 1, 2016: British Journal of Haematology
https://www.readbyqxmd.com/read/27873493/decitabine-as-a-first-line-treatment-for-older-adults-newly-diagnosed-with-acute-myeloid-leukemia
#16
Hyunsung Park, Haerim Chung, Jungyeon Lee, Jieun Jang, Yundeok Kim, Soo Jeong Kim, Jin Seok Kim, Yoo Hong Min, June Won Cheong
PURPOSE: Decitabine, a DNA hypomethylating agent, was recently approved for use in Korea for older adults with acute myeloid leukemia (AML) who are not candidates for standard chemotherapy. This study aimed to evaluate the role of decitabine as a first-line treatment for older adults with AML. MATERIALS AND METHODS: Twenty-four patients with AML who received at least one course of decitabine (20 mg/m²/d intravenously for 5 days every 4 weeks) as a first-line therapy at Severance Hospital were evaluated retrospectively...
January 2017: Yonsei Medical Journal
https://www.readbyqxmd.com/read/27849645/current-management-of-patients-with-chronic-myelomonocytic-leukemia
#17
Ana Alfonso, Guillermo Montalban-Bravo, Guillermo Garcia-Manero
PURPOSE OF REVIEW: The present review will focus on the current management of patients with chronic myelomonocytic leukemia (CMML) as well as in future therapeutic perspectives. RECENT FINDINGS: CMML is a clonal hematopoietic stem cell disorder characterized by peripheral blood monocytosis and myelodysplastic and myeloproliferative alterations in the bone marrow. Clinical behavior of the disease can be heterogeneous, with some patients having an indolent form of the disease, whereas others experience an aggressive course with decreased survival and eventual transformation to leukemia...
January 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/27835920/-acute-myeloid-leukemia
#18
Jan Braess
Acute myeloid leukemia (AML) has been genetically characterized extensively and can now be subdivided into 9 to 11 pathogenetically different subtypes according to their profile of driver mutations. In clinical practice karyotyping and molecular analysis of NPM1, cEBPa and FLT3-ITD are required for treatment stratification and potentially genotype specific treatment. Some markers such as NPM1 not only offer prognostic information but can also serve as markers of minimal residual disease and thus have the potential to guide therapy in the future...
November 2016: Deutsche Medizinische Wochenschrift
https://www.readbyqxmd.com/read/27812249/the-synergistic-effects-of-decitabine-combined-with-arsenic-trioxide-ato-in-the-human-myelodysplastic-syndrome-cell-line-skm-1
#19
Ping Wu, Long Liu, Jianyu Weng, Suxia Geng, Chengxin Deng, Zesheng Lu, Chengwei Luo, Xin Du
Despite recent advances in the treatment of myelodysplastic syndrome (MDS), single-agent clinical effects remain unsatisfactory, and decitabine monotherapy is also associated with a relatively low rate of complete remission. To study the combined effects and mechanism of decitabine (DAC) and arsenic trioxide (ATO) on the human myelodysplastic cell line SKM-1,we used the MTS assay and CalcuSyn software to determine the cytotoxicity and potential synergistic effects, respectively. Furthermore, we determined apoptosis and measured the mRNA expression level of two genes that are considered main regulators of the apoptosis process...
December 2016: Indian Journal of Hematology & Blood Transfusion
https://www.readbyqxmd.com/read/27808592/pd1-and-pdl1-upregulation-and-survival-after-decitabine-treatment-in-lower-risk-mds
#20
Sameem Abedin, Leonidas C Platanias
No abstract text is available yet for this article.
November 3, 2016: Leukemia & Lymphoma
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