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Antimetabolites
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Azacitidine (VidazaTM) is similar in structure to cytarabine, but a heterocyclic nitrogen has been inserted at the 5-position of the pyrimidine ring (to form a triazine) and the C2′-hydroxy group on the sugar moiety has been inverted compared to cytarabine (Figure 3.11). It is also a C2′-deoxy derivative of decitabine, which is a DNA hypomethylating agent.
The Emerging Role of Histone Deacetylase Inhibitors in the Treatment of Lymphoma
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Butyrate, phenylbutyrate, and valproic acid were among the first drugs that were shown to have HDAC inhibitory activity, with phenylbutyrate and valproate having a significant clinical experience in cervical (33) and breast cancers, melanoma, and other solid tumors (34). In hematologic malignancies, valproate has been used in the treatment of AML with all-transretinoic acid (ATRA) producing one complete remission (CR) and a response rate of 5% (35). Other studies in patients with AML studied combinations with valproate and the hypomethylating agent 5-aza-2′-deoxycytidine with an overall response rate (ORR) of 22%, and a remarkable CR rate of 19% (36). A recent report by Zain et al. described a CR in a patient with diffuse large B-cell lymphoma refractory to previous lines of therapy following monotherapy with valproate alone (37).
Chronic Myeloid Leukaemia
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Whilst qualified responses with TKIs have been observed in patients with CML in the accelerated phase, most tend not to be durable. The activity of TKIs in BT is even less impressive with a median survival of less than 9 months. Currently, both dasatinib and bosutinib, but not nilotinib are licensed for BT. Another useful drug licensed for CP and accelerated phase disease-resistant to at least two TKIs, is omacetaxine mepesuccinate, an inhibitor of protein synthesis. The drug is often associated with severe myelosuppression, which has limited its use. In younger patients, it might be reasonable to offer patients in frank BT, and an acute leukaemia type of chemotherapy in combination with a TKI which they might not have received prior to BT, or an appropriate clinical trial assessing one of the newer drugs and then consider allo-SCT if a second CP is achieved. At present, the MD Anderson Hospital (Houston) has a TKI plus hypomethylating agent trial underway that looks promising, but clearly, it is difficult to make firm recommendations at present. Lastly, a report from Peter Valent (Vienna) of the use of a rotation of ponatinib and bosutinib, to induce persistent deep MR in an older patient with multi-resistant blast crisis, is interesting and merits further study.
Efficacy and safety of an HDACi- and HMA-based protocol in adults with acute myeloid leukemia of intermediate- and adverse-risk categories: a retrospective study
Published in Hematology, 2023
Zhibo Guo, Dan Guo, Desheng Kong, Sicheng Bian, Leilei Lin, Shengjin Fan, Qi Li, Yanqiu Zhao, Yanmeng Jiang, Jiangrong Yan, Zheren Wang, Lili Sun, Yinghua Li
Genomic and epigenetic alterations participate in the occurrence and progression of hematological malignancies [8–11]. Hypomethylating agent (HMA) decitabine works by binding to DNA methyltransferase [12], thus specifically inducing cell cycle arrest, activating tumor suppressor genes, and inhibiting the proliferation of tumor cells [13,14]. Mutations such as DNMT3A, TET2 are related to functions of DNA methylation, and HMA has shown efficacy for patients with mutation mentioned above [15]. Decitabine has been approved as a favorable agent by the Food and Drug Administration for clinical treatments of AML (combined with venetoclax for patients intolerant for intense chemotherapy), myelodysplastic syndromes. Clinical trials related to decitabine combined with chemotherapy (such as FLAG, DA and CAG) for newly diagnosed or relapsed/refractory AML (R/R AML) achieved better outcomes [16–18].
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].
Perspectives on PARP inhibitors as pharmacotherapeutic strategies for breast cancer
Published in Expert Opinion on Pharmacotherapy, 2021
Sun Young Oh, Shafia Rahman, Joseph A. Sparano
Hypomethylating agent inhibits DNA methylation and induce DNA damage by inactivating and trapping DNA methyltransferase (DNMT) to DNA, with the damaged DNA being repaired by the base excision repair (BER) machinery. PARP inhibitor disrupts the repair of hypomethylating agent-induced DNA methyltransferase DNA lesions by preventing relocation of the BER enzyme XRCC1 to DNA damage sites. The combination of PARP inhibitor with the hypomethylating agent provided synergistic cytotoxicity [122,123]. Preclinical data showed combination of DNMT inhibition and talazoparib significantly reduced cell colony in ovarian cancer regardless BRCA and platinum sensitivity status. ASTX727 is a novel agent, a combination of the hypomethylating agent decitabine and the novel cytidine deaminase inhibitor, E7727 (cedazuridine). Safety of combination therapy of ASTX727 plus talazoparib in patients with TNBC or hormone-resistant/HER2 negative metastatic breast cancer is being conducted (NCT04134884).