Nucleic Acids as Therapeutic Targets and Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
After 5-azanucleosides such as 5-azacitidine have been metabolized to 5-aza-2′-deoxycytidine-triphosphate (i.e., decitabine-triphosphate), they can be incorporated into DNA. Azacytosine-guanine dinucleotides are recognized as a substrate by the DNA methyltransferases which catalyze the methylation reaction through a nucleophilic attack. This results in a covalent bond between the C5-atom of the cytosine ring and the enzyme which is normally resolved by β-elimination through the C5-atom. However, this latter reaction does not occur with 5-azacytosine because its C5-position is substituted by nitrogen, leaving the enzyme covalently bound to DNA and blocking its DNA methyltransferase function. Furthermore, the covalent protein adduct compromises the functionality of DNA and triggers DNA damage signaling, resulting in the degradation of trapped DNA methyltransferases. Thus, methylation marks become lost during DNA replication. Azacitidine has a number of side effects including anemia, neutropenia, and thrombocytopenia, so patients require frequent monitoring of blood counts. Other side effects include GI symptoms (e.g., nausea, vomiting, constipation, and diarrhea), fever, bruising, petechiae, rigors, fatigue, and abnormally low potassium levels.
Leukaemias
Pat Price, Karol Sikora in Treatment of Cancer, 2014
The DNA hypomethylating pyrimidine analogues 5-azacytidine (azacitidine) and 5-aza-2-deoxycytidine (decitabine) have both been extensively investigated in patients with MDS over the past decade. The drugs reduce hypermethylation and induce re-expression of tumour suppressor genes. Earlier phase II studies confirmed the efficacy of both drugs in benefitting patients with RBC-transfusion dependence and also improvements in other cytopenias while suppressing bone marrow blasts.206 In a large international randomized study, treatment with 5-azacitidine was compared with ‘conventional’ care, the latter of which included ‘best’ supportive care, low dose cytarabine and intensive chemotherapy, in patients with ‘higher-risk’ disease.207 Median survival was 24.5 months in the azacitidine arm compared to 15.0 months in the control arm (p = .0001). In addition, there was a significant extension in the interval to AML transformation in the azacitidine arm compared to the best supportive care (17.8 months vs. 11.5 months; p = .004). The most common grade 3/4 side effect associated with azacitidine was cytopenias. In a randomized study of patients with intermediate-1, intermediate-2 and high-risk disease comparing decitabine with best supportive care, the partial and complete response rate was 17% in the decitiabine arm. Although decitabine treated patients tended to have a longer median time to AML transformation compared to the supportive care arm, there was no difference in overall survival.208 In another more recent similar randomized study involving older patients in both ‘lower-risk’ and ‘higher-risk’, there were also no overall survival differences.209 Based on the available data, the 2013 ELN MDS guidelines support the use of azacitidine over decitabine for ‘higher-risk’ patients who are not eligible for allo-SCT.191 Both drugs appear reasonable for the ‘lower-risk’ patients who are resistant/refractory to growth factors or lenalidomide. Very recently, azacitidine was also shown to overcome the dismal outcome in high-risk MDS patients with chromosomal 3q abnormality and EVI-1, a potent epigenetic modifier.210
Application of prophylactic or pre-emptive therapy after allogeneic transplantation for high-risk patients with t(8;21) acute myeloid leukemia
Published in Hematology, 2023
Wenwen Guo, Xin Liu, Mingyang Wang, Jia Liu, Yigeng Cao, Yawei Zheng, Weihua Zhai, Xin Chen, Rongli Zhang, Qiaoling Ma, Donglin Yang, Jialin Wei, Yi He, Aiming Pang, Sizhou Feng, Mingzhe Han, Erlie Jiang
Broadly speaking, maintenance therapy includes pre-emptive therapy (based on MRD) and prophylactic therapy (not based on MRD) [12]. Emerging studies have shown that high-risk AML patients may benefit from maintenance therapy after allo-HCT because it can induce graft versus leukemia (GVL) effect and eradicate persistent MRD [13, 14]. Considering the risk of unnecessary exposure to treatment, pre-emptive interventions directed by MRD after allo-HCT are more common. However, no comparison has been made between the suitability of prophylactic and pre-emptive therapy for use in AML patients. Besides, studies reporting the utility of prophylactic and pre-emptive strategies in a specific disease setting, such as t(8;21) AML, are limited [15]. Azacitidine (AZA), a hypomethylating agent, is commonly used as a maintenance drug in AML patients. Moreover, studies have demonstrated the feasibility of pre-emptive AZA use in patients with high-risk AML and myelodysplastic syndromes (MDS) [16, 17]. As a novel histone deacetylase inhibitor, chidamide has been proven to inhibit AML cell proliferation and induce cell apoptosis [18, 19]. A phase 2 trial reported that the double epigenetic priming regimen, which included chidamide, showed superior anti-leukemia activity. In our study, epigenetic drugs, including AZA and chidamide, were used as prophylactic agents. Therefore, we aimed to investigate the influence of pre-MRD on the outcomes of t(8;21) AML patients, in addition to evaluating the efficacy of maintenance therapy, including pre-emptive and prophylactic interventions, after allo-HCT.
Low serum albumin level deteriorates prognosis in azacitidine-treated myelodysplastic syndromes patients – results of the PALG study ‘PolAZA’
Published in Hematology, 2021
Krzysztof Mądry, Karol Lis, Andrzej Tukiendorf, Paweł Szwedyk, Katarzyna Kapelko-Słowik, Edyta Subocz, Aleksandra Gołos, Wioletta Makowska, Anna Masternak, Anna Kopińska, Magdalena Czemerska, Sara Zawadzka-Leska, Patrycja Rusicka, Joanna Drozd-Sokołowska, Elżbieta Wiater, Jadwiga Hołojda, Bartłomiej Pogłódek, Piotr Centkowski, Anna Waszczuk-Gajda, Rafał Machowicz, Janusz Hałka, Tomasz Czerw, Grzegorz Basak, Jadwiga Dwilewicz-Trojaczek
Azacitidine is the standard of care for patients with higher risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML) who are not eligible for intensive chemotherapy or hematopoietic stem cell transplantation. A large randomized trial AZA-001 showed survival benefit of azacitidine treatment when compared with conventional treatments with a median survival 24.5 months [1]. On the other hand, overall survival was shorter in smaller randomized trials and real-life studies (15–20 and 13–17 months, respectively) [2–4]. In this context, both pre-treatment as well as on-treatment risk stratification and identification of factors predicting response and prognosis seem to be of special value. It can be especially helpful for ‘borderline’ candidates for allogeneic transplantation at the age of 60–75 years with comorbidities. Many previous studies analyzing prognostication of azacitidine-treated patients focused only on selected parameters. The present study takes advantage of a large multicenter cohort of MDS/AML/CMML azacitidine-treated patients and analyzes in a complex way the patient-, disease-. and treatment-related factors that might affect the clinical outcome.
Cost-effectiveness analysis of azacitidine maintenance therapy in patients with acute myeloid leukemia
Published in Expert Review of Hematology, 2022
Jinbing Zhu, Qiuji Wu, Jinjin Wang, Ting Niu
Azacitidine exerts its anti-tumor effects by inhibiting DNA methyltransferase [34,35]. However, azacitidine alone has only amodest effect in newly diagnosed AML patients, with an overall response rate about 20% [3]. During induction chemotherapy, azacitidine is now used as a combination therapy with other target drugs to reduce tumor burden [3,12,34,36]. Combining azacitidine with venetoclax has been proven effective as an induction treatment in AML patients who are not fit for intensive chemotherapy [12]. When AML patients who cannot be treated with high-dose chemotherapy achieved CR after induction therapy, azacitidine or decitabine is recommended as maintenance therapy by the National Comprehensive Cancer Network (NCCN) before the approval of oral azacitidine. In September 2020, the US FDA approved oral azacitidine in the maintenance therapy for AML at their first remission based on the QUAZAR AML-001 trial [16,17].
Related Knowledge Centers
- Cytidine
- Decitabine
- DNA
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- Nucleoside
- Rna
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- Medication
- Juvenile Myelomonocytic Leukemia
- Structural Analog