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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
5-Azacytidine is a chemical analog of cytidine (a nucleoside component of DNA and RNA), and becomes incorporated into genomic DNA. It is used, along with its deoxy derivative decitabine (DacogenTM) (Figure 5.110) for the treatment of myelodysplastic syndrome for which it received approval from the FDA in 2004. Both agents were first synthesized in Czechoslovakia as potential antimetabolite agents. In two pivotal randomized controlled clinical trials comparing azacitidine to supportive treatment, 16% of patients with myelodysplastic syndrome who received azacitidine had a complete or partial normalization of bone marrow morphology and blood cell counts compared to 0% who received supportive care. Importantly, approximately two-thirds of patients who would normally require blood transfusions did not need one after azacitidine treatment. 5-Azacytidine is also sometimes used for the treatment of acute myeloid leukemia.
General Biological Aspects of Oncogenesis
Published in Pimentel Enrique, Oncogenes, 2020
DNA alkylation may produce changes in the patterns of DNA-protein interaction, including the function of DNA methylating enzymes. A single treatment of human cells (Raji lymphoblastic cells) with TV-methyl-Af-nitrosourea (NMU) results in inhibition of methylation of internal cytosines at 5’-CCGG-3’ sequences of DNA.198 The consequent aberrant patterns of DNA methylation may be reflected in altered patterns of genome expression, which could eventually lead to a heritable malignant behavior of the cell. A similar phenomenon could be involved in the mechanisms of action of other carcinogens, including ethionine and 2-(acetylamino)fluorene (AAF).200,201 5-azacytidine is known to inhibit DNA methylation and to activate the expression of cellular or viral genes, and it is also capable of inducing a diversity of tumors in rats, acting as a complete carcinogen.197,202 Treatment of human cell lines with 5-azacytidine may result in profound alterations in clonogenicity and growth rate,203 probably by activation of gene sets involved in the control of cell proliferation.
Drug profiles: generic names A-Z
Published in Jerome Z. Litt, Neil H. Shear, Litt's Drug Eruption & Reaction Manual, 2017
Clinically important, potentially hazardous interactions with: alefacept, aminophylline, azacitidine, betamethasone, cabazitaxel, cefazolin, cefixime, ceftaroline fosamil, ceftobiprole, ciprofloxacin, demeclocycline, denileukin, docetaxel, doripenem, doxycycline, fingolimod, gefitinib, gemifloxacin, leflunomide, levofloxacin, monosodium glutamate, moxifloxacin, ofloxacin, oxaliplatin, pazopanib, sulfadiazine, telavancin, telithromycin, temsirolimus
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.
Non-intensive acute myeloid leukemia therapies for older patients
Published in Expert Review of Hematology, 2023
Rodrick Babakhanlou, Farhad Ravandi-Kashani
The ASTRAL-1 trial, a randomized phase 3 trial intended to compare Guadecitabine against treatment of choice, which included azacitidine, decitabine, or LDAC for the management of newly diagnosed AML in elderly unfit patients ineligible for intensive chemotherapy [55]. This led to an indirect comparison of azacitidine and decitabine. Azacitidine was given intravenously or subcutaneously at 75 mg/m2 per day on days 1 to 7. Decitabine was given intravenously at 20 mg/m2 per day on days 1 to 5. There were no significant differences in the CR rate and OS between both groups. Serious adverse events leading to death seemed to be more frequent in the azacitidine group. Data of this trial suggested that azacitidine and decitabine can be used interchangeably among older and unfit AML patients [55].
Advances in myelodysplastic syndromes: promising novel agents and combination strategies
Published in Expert Review of Hematology, 2023
Yazan F. Madanat, Zhuoer Xie, Amer M. Zeidan
Patients with high-risk MDS (IPSS risk of intermediate-II/high risk or IPSS-R intermediate [score ≥4.0], high, very-high risk) have dismal outcomes without treatment [18,19]. The mainstay therapy has been initiation of hypomethylating agent therapy with azacitidine, decitabine, or oral decitabine (ASTX727, decitabine-cedazuridine) to improve survival and delay AML progression [41,70–73]. Response rates of hypomethylating agent therapy are modest and while the AZA001 MDS trial demonstrated a 9.5-month improvement in OS, large retrospective and population-based studies showed a less impressive OS advantage and no significant differences between IV decitabine and IV or SC azacitidine [74–76]. Real-world data of using azacitidine suggest a shorter OS is seen compared to AZA001, and median OS was improved for patients receiving 4 or more cycles of therapy reaching 18 months [77]. Similar results were reported in a large systematic review of using azacitidine in 16 different studies, half of which had real-world data. The median OS was only 16.4 months [78]. A recent trial comparing 5 vs 7 day azacitidine schedule was terminated early due to slow accrual, and therefore a 7-day course of azacitidine remains the standard of care on a 7-day consecutive or a 5-2-2 (weekend off) schedule [79]. Allogeneic hematopoietic is recommended upfront for patients up to the age of 75 based on the results of the Blood and Marrow Transplant Clinical Trials Network Study 1102 where OS at 3 years following treatment assignment in the donor arm was significantly higher than in the no donor arm (47.9% vs 26.6%, p = .0001) [80].