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Xenobiotica; the Fate of Foreign... Jan 20221. NDec is a novel, oral, fixed-dose formulation of decitabine and tetrahydrouridine that is currently being developed for the treatment of patients with sickle cell...
1. NDec is a novel, oral, fixed-dose formulation of decitabine and tetrahydrouridine that is currently being developed for the treatment of patients with sickle cell disease. Here, we examine the potential for both components of NDec to interact with key drug metabolising enzymes (tetrahydrouridine only) and drug transporters (decitabine and tetrahydrouridine).2. This study assessed the inhibition and induction of cytochrome P450 (CYP) enzymes by tetrahydrouridine, as well as the involvement of specific drug metabolising enzymes in tetrahydrouridine metabolism. Inhibition of efflux and uptake transporters by both decitabine and tetrahydrouridine was also studied.3. Tetrahydrouridine did not inhibit or induce relevant CYP enzymes at concentrations ranging from 0.1 to 100 μM. Metabolism of tetrahydrouridine did not occur in the presence of the human drug metabolising enzymes tested. Tetrahydrouridine showed weak inhibition towards the MATE2-K transporter (∼30% inhibition at 5 and 50 μM), which was not deemed clinically relevant. Tetrahydrouridine did not inhibit any of the remaining uptake or efflux transporters. Decitabine (0.5 and 5 μM) did not inhibit any of the evaluated uptake or efflux drug transporters.4. Data presented confirm that tetrahydrouridine and decitabine are unlikely to be involved in metabolism- or transporter-based drug-drug interactions.
Topics: Biological Transport; Decitabine; Drug Interactions; Humans; Membrane Transport Proteins; Tetrahydrouridine
PubMed: 34913834
DOI: 10.1080/00498254.2021.2018628 -
Clinical Epigenetics May 2023Targeting the epigenome of cancerous diseases represents an innovative approach, and the DNA methylation inhibitor decitabine is recommended for the treatment of...
BACKGROUND
Targeting the epigenome of cancerous diseases represents an innovative approach, and the DNA methylation inhibitor decitabine is recommended for the treatment of hematological malignancies. Although epigenetic alterations are also common to solid tumors, the therapeutic efficacy of decitabine in colorectal adenocarcinomas (COAD) is unfavorable. Current research focuses on an identification of combination therapies either with chemotherapeutics or checkpoint inhibitors in modulating the tumor microenvironment. Here we report a series of molecular investigations to evaluate potency of decitabine, the histone deacetylase inhibitor PBA and the cytidine deaminase (CDA) inhibitor tetrahydrouridine (THU) in patient derived functional and p53 null colon cancer cell lines (CCCL). We focused on the inhibition of cell proliferation, the recovery of tumor suppressors and programmed cell death, and established clinical relevance by evaluating drug responsive genes among 270 COAD patients. Furthermore, we evaluated treatment responses based on CpG island density.
RESULTS
Decitabine caused marked repression of the DNMT1 protein. Conversely, PBA treatment of CCCL recovered acetylation of histone 3 lysine residues, and this enabled an open chromatin state. Unlike single decitabine treatment, the combined decitabine/PBA treatment caused > 95% inhibition of cell proliferation, prevented cell cycle progression especially in the S and G2-phase and induced programmed cell death. Decitabine and PBA differed in their ability to facilitate re-expression of genes localized on different chromosomes, and the combined decitabine/PBA treatment was most effective in the re-expression of 40 tumor suppressors and 13 genes typically silenced in cancer-associated genomic regions of COAD patients. Furthermore, this treatment repressed expression of 11 survival (anti-apoptotic) genes and augmented expression of X-chromosome inactivated genes, especially the lncRNA Xist to facilitate p53-mediated apoptosis. Pharmacological inhibition of CDA by THU or its gene knockdown prevented decitabine inactivation. Strikingly, PBA treatment recovered the expression of the decitabine drug-uptake transporter SLC15A1, thus enabling high tumor drug-loads. Finally, for 26 drug responsive genes we demonstrated improved survival in COAD patients.
CONCLUSION
The combined decitabine/PBA/THU drug treatment improved drug potency considerably, and given their existing regulatory approval, our findings merit prospective clinical trials for the triple combination in COAD patients.
Topics: Humans; Decitabine; Azacitidine; Histone Deacetylases; Cytidine Deaminase; Tumor Suppressor Protein p53; Prospective Studies; DNA Methylation; Histone Deacetylase Inhibitors; Tetrahydrouridine; Epigenesis, Genetic; Adenocarcinoma; Colorectal Neoplasms; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37208732
DOI: 10.1186/s13148-023-01500-1 -
Future Oncology (London, England) Jan 2023The management of patients with acute myeloid leukemia (blast phase) secondary to myeloproliferative neoplasms (MPNs) is extremely challenging and the outcome dismal,... (Review)
Review
The management of patients with acute myeloid leukemia (blast phase) secondary to myeloproliferative neoplasms (MPNs) is extremely challenging and the outcome dismal, with a median overall survival of about 3-6 months. Effective therapeutic approaches are lacking, especially when intensive strategies followed by allogeneic transplantation are not feasible. The combination of venetoclax and hypomethylating agents has recently been established as standard for newly diagnosed, unfit patients with acute myeloid leukemia, but the application of this therapeutic modality has not been tested prospectively in the specific context of blast-phase MPNs. ENABLE is an open, phase II clinical trial aimed at verifying the efficacy and safety of the combination of venetoclax and decitabine in patients with post-MPN blast phase.
Topics: Humans; Decitabine; Blast Crisis; Leukemia, Myeloid, Acute; Bridged Bicyclo Compounds, Heterocyclic; Myeloproliferative Disorders; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36651780
DOI: 10.2217/fon-2022-0512 -
Leukemia & Lymphoma Dec 2023We retrospectively analyzed the outcomes of 136 consecutive patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our center. Among...
We retrospectively analyzed the outcomes of 136 consecutive patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our center. Among them, 76 cases used hypomethylating agents (decitabine, = 40; azacitidine, = 36) as post-transplant maintenance therapy, whereas 60 contemporaneous patients did not adopt maintenance therapy. The 3-year incidences of relapse in two groups were 16.6% and 39.2% ( = .001). The 3-year OS and DFS in maintenance group were 84.0% and 78.6%, which were remarkably improved than in control group (60.0% and 58.0%) ( = .004, = .011). Moreover, the 3-year relapse rates for patients receiving decitabine and azacitidine therapy were 8.5% and 25.0%, respectively ( = .019). Patients utilizing decitabine had more common possibility of grade 3-4 neutropenia than azacitidine (20.0% vs. 2.8%, = .031). These results indicate that maintenance therapies using hypomethylating agents could reduce the risk of post-transplant recurrence, resulting into remarkable superior survival. Decitabine might lower relapse after allo-HSCT with somewhat more severe myelosuppression when being compared to azacitidine.
Topics: Humans; Decitabine; Myelodysplastic Syndromes; Retrospective Studies; Transplantation, Homologous; Hematopoietic Stem Cell Transplantation; Azacitidine; Leukemia, Myeloid, Acute; Recurrence
PubMed: 37732615
DOI: 10.1080/10428194.2023.2252948 -
Clinical Lymphoma, Myeloma & Leukemia Jun 2021Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies that mostly affect the elderly and have a poor prognosis. Azacitidine (AZA)... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies that mostly affect the elderly and have a poor prognosis. Azacitidine (AZA) and decitabine (DAC) are the most widely used hypomethylating agents. However, few randomized controlled trials (RCTs) have compared AZA and DAC head to head in MDS or AML. This study intended to conduct a network meta-analysis to compare the 2 drugs to provide more guidance using evidence-based medicine.
PATIENTS AND METHODS
A comprehensive search for RCTs was performed till July 31, 2020. The network meta-analysis was conducted using the Markov chain Monte Carlo method. The primary endpoints were overall survival (OS) and the incidence of adverse events, and the secondary endpoints were complete remission (CR) rate, overall remission rate (ORR), and AML-free survival. There were 6 RCTs with 1072 MDS patients, and 3 RCTs with 1256 AML patients.
RESULTS
In MDS, AZA showed better AML-free survival (hazard ratio = 0.62; 95% CI, 0.43-0.9), whereas DAC had the possibility of achieving better CR and ORR, and AZA had the possibility of obtaining better OS with lower toxicity. As for elderly AML patients, DAC had the possibility of achieving superior CR, ORR, and OS, while the toxicity was relatively higher. Furthermore, subgroup analysis for patients ≥ 75 years old or of high risk in MDS suggested that AZA achieved better OS.
CONCLUSION
For MDS, especially patients with intermediate or high risk disease with advanced age and poor general condition, AZA may be a better choice, while DAC may be of more benefit in elderly AML patients.
Topics: Age Factors; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Decitabine; Disease Management; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Odds Ratio; Prognosis; Treatment Outcome
PubMed: 33716056
DOI: 10.1016/j.clml.2021.01.024 -
Critical Reviews in Oncology/hematology Aug 2019The hypomethylating agents (HMAs), decitabine and azacitidine, are valuable treatment options in acute myeloid leukemia patients who are not eligible for intensive... (Review)
Review
The hypomethylating agents (HMAs), decitabine and azacitidine, are valuable treatment options in acute myeloid leukemia patients who are not eligible for intensive chemotherapy. Both agents are generally well tolerated, and complications most commonly relate to myelosuppression. Antibiotic / antifungal use, regular monitoring, and proactive patient education are important to minimize these events, and reduce the need for dose delay. Responses to HMAs are often not evident for up to 6 cycles, and there is currently no validated clinical marker for predicting response. Hence, treatment should be continued for at least 4-6 cycles to ensure that patients have sufficient opportunity to respond. Delivery of insufficient numbers of cycles is a key reason for HMA failure, and premature discontinuation must be avoided. Genetic factors offer potential for better predicting responders to HMAs in future, but require further study.
Topics: Azacitidine; DNA Methylation; Decitabine; Humans; Leukemia, Myeloid, Acute
PubMed: 31153036
DOI: 10.1016/j.critrevonc.2019.05.013 -
Endocrine-related Cancer Jun 2023Anaplastic thyroid cancer (ATC) is one of the most aggressive solid cancers in humans, with limited treatment options. Recent studies suggest that cancer stem cell (CSC)...
Anaplastic thyroid cancer (ATC) is one of the most aggressive solid cancers in humans, with limited treatment options. Recent studies suggest that cancer stem cell (CSC) activity contributes to therapeutic resistance and recurrence of ATC. We show that the expression of the endogenous thyroid hormone receptor β gene (THRB) is silenced in ATC and demonstrate that the exogenously expressed TRβ suppresses CSC activity. Decitabine is one of the demethylation agents to treat myelodysplastic syndrome and acute myeloid leukemia patients and is currently in clinical trials for hematopoietic malignancies and solid tumors. We aim to show that the re-expression of the endogenous THRB gene by decitabine can attenuate CSC activity to block ATC tumor growth. We treated ATC cell lines derived from human ATC tumors (11T and 16T cells) with decitabine and evaluated the effects of the reactivated endogenous TRβ on CSC activity in vitro and in vivo xenograft models. We found that treatment of 11T and 16T cells with decitabine reactivated the expression of endogenous TRβ, as evidenced by western blot and immunohistochemical analyses. The expressed TRβ inhibited cell proliferation by arresting cells at the S phase, increased apoptotic cell death by upregulation of cleaved caspase-3, and markedly suppressed the expression of CSC regulators, including cMYC, ALDH, SOX2, CD44, and β-catenin. Decitabine also inhibited xenograft tumor growth by suppressing CSC activity, inhibiting cancer cell proliferation, and increasing apoptosis. Our findings suggest that re-expression of the endogenous TRβ is a novel therapeutic approach for ATC via suppression of CSC activity.
Topics: Humans; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Thyroid Hormone Receptors beta; Genes, erbA; Decitabine; Cell Line, Tumor; Neoplastic Stem Cells; Apoptosis; Cell Proliferation
PubMed: 36939877
DOI: 10.1530/ERC-22-0306 -
Acta Haematologica 2021Treatment options are limited for patients with advanced forms of myeloproliferative neoplasms (MPN) including blast-phase disease (MPN-BP). Decitabine has frequently...
Treatment options are limited for patients with advanced forms of myeloproliferative neoplasms (MPN) including blast-phase disease (MPN-BP). Decitabine has frequently been deployed but its efficacy and safety profile are not well described in this population. We retrospectively reviewed 42 patients treated with decitabine either alone or in combination with ruxolitinib at our institution: 16 with MPN-BP, 14 with MPN accelerated-phase (MPN-AP), and 12 with myelofibrosis with high-risk features (MF-HR). The median overall survival (OS) for the MPN-BP patients was 2.6 months, and for those who received ≥2 cycles of decitabine therapy, it was 6.7 months (3.8-29.8). MPN-BP patients with a poor performance status and who required hospitalization at the time of the initiation of decitabine had a dismal prognosis. After a median follow-up of 12.4 months for MPN-AP patients, and 38.7 months for MF-HR patients, the median OS was not reached for either cohort, with 1 and 2 patients alive at 60 months, respectively. The probability of spleen length reduction and transfusion independence within 12 months of initiating decitabine was 28.6 and 23.5%, respectively. The combination of decitabine and ruxolitinib appeared to improve overall survival versus single-agent decitabine (21 and 12.9 months, respectively). Decitabine, alone or in combination with ruxolitinib, appears to have clinical benefit for patients with advanced phases of MPN when initiated early in the disease course prior to the development of MPN-BP.
Topics: Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Biomarkers; Chromosome Aberrations; Combined Modality Therapy; Decitabine; Female; Gene Expression Profiling; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Myeloproliferative Disorders; Neoplasm Staging; Prognosis; Retreatment; Retrospective Studies; Treatment Outcome
PubMed: 32160610
DOI: 10.1159/000506146 -
Scientific Reports Nov 2022Computational analysis of drug solubility was carried out using machine learning approach. The solubility of Decitabine as model drug in supercritical CO was studied as...
Computational analysis of drug solubility was carried out using machine learning approach. The solubility of Decitabine as model drug in supercritical CO was studied as function of pressure and temperature to assess the feasibility of that for production of nanomedicine to enhance the solubility. The data was collected for solubility optimization of Decitabine at the temperature 308-338 K, and pressure 120-400 bar used as the inputs to the machine learning models. A dataset of 32 data points and two inputs (P and T) have been applied to optimize the solubility. The only output is Y = solubility, which is Decitabine mole fraction solubility in the solvent. The developed models are three models including Kernel Ridge Regression (KRR), Decision tree Regression (DTR), and Gaussian process (GPR), which are used for the first time as a novel model. These models are optimized using their hyper-parameters tuning and then assessed using standard metrics, which shows R-score, KRR, DTR, and GPR equal to 0.806, 0.891, and 0.998. Also, the MAE metric shows 1.08E-04, 7.40E-05, and 9.73E-06 error rates in the same order. The other metric is MAPE, in which the KRR error rate is 4.64E-01, DTR shows an error rate equal to 1.63E-01, and GPR as the best mode illustrates 5.06E-02. Finally, analysis using the best model (GPR) reveals that increasing both inputs results in an increase in the solubility of Decitabine. The optimal values are (P = 400, T = 3.38E + 02, Y = 1.07E-03).
Topics: Solubility; Solvents; Decitabine; Computer Simulation; Machine Learning
PubMed: 36344531
DOI: 10.1038/s41598-022-21233-0 -
Leukemia & Lymphoma Mar 2023Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are devastating diseases that frequently rely on the use of parenteral hypomethylating agents (HMAs),...
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are devastating diseases that frequently rely on the use of parenteral hypomethylating agents (HMAs), either as monotherapy or in combination, as first-line treatment for many patients. Two new oral HMAs, decitabine/cedazuridine (DC) for use in place of azacitidine or decitabine in MDS, and azacitidine (CC-486) for use as maintenance treatment in AML, were recently approved by the FDA. We will discuss the development of these oral HMAs, including the advantages/disadvantages in transitioning to oral HMAs and an in depth look at the pivotal phase III trials that led to their FDA approval - ASCERTAIN for DC and QUAZAR-AML-001 for CC-486. We also review how these agents have been and are being studied in other malignancies, and examine the future role that these exciting novel agents will play in both MDS and AML.
Topics: Humans; Decitabine; Antimetabolites, Antineoplastic; Azacitidine; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute
PubMed: 36370098
DOI: 10.1080/10428194.2022.2142051