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Clinical Immunology (Orlando, Fla.) May 2023Psoriasis is a chronic inflammatory skin disease mediated by immune and complex genetic factors. The wingless-related integration site (Wnt) signaling pathway plays a...
Psoriasis is a chronic inflammatory skin disease mediated by immune and complex genetic factors. The wingless-related integration site (Wnt) signaling pathway plays a critical role in psoriasis, but how the Wnt pathway is regulated in psoriatic skin and whether it can be exploited for therapeutic benefits is unclear. By comparing biopsies from healthy and psoriatic skin, we found that Wnt inhibitory factor 1 (WIF1), an inhibitor of Wnt signaling, showed reduced expression at both mRNA and protein levels in psoriatic skin. We then quantified methylation of the WIF1 gene promoter by DNA methylation sequencing and found that the WIF1 promoter region was hypermethylated. We further showed that recombinant WIF1 injection ameliorates the imiquimod (IMQ) mouse model of psoriasis. We also revealed that treatment with the DNA methylation inhibitor, decitabine, inhibited proliferation of immortalized human keratinocytes (HaCaT) in a psoriasis-like inflammatory environment. Finally, we applied decitabine to the IMQ mouse model and demonstrated that treatment of mice with decitabine ameliorates the disease. Therefore, our study reveals that methylation of the WIF1 gene is associated with the pathogenesis of psoriasis, and suggests that pharmacological targeting of DNA methylation is a potential treatment strategy for psoriasis.
Topics: Humans; Animals; Mice; Decitabine; Psoriasis; Skin; Keratinocytes; DNA Methylation; Imiquimod; Promoter Regions, Genetic; Mice, Inbred BALB C; Disease Models, Animal
PubMed: 36925027
DOI: 10.1016/j.clim.2023.109294 -
Best Practice & Research. Clinical... Dec 2019Patients diagnosed with myelodysplastic syndromes (MDS) often ask their physicians whether earlier detection of disease or more prompt initiation of treatment might have... (Review)
Review
Patients diagnosed with myelodysplastic syndromes (MDS) often ask their physicians whether earlier detection of disease or more prompt initiation of treatment might have resulted in a better outcome. The concept of starting therapy at an early point in the disease process when the clonal burden of abnormal hematopoietic stem cells may be lower and somatic mutational complexity less, and therefore treatment more likely to be effective, is attractive. However, at present there is no evidence that therapy with any of the available drugs for MDS (ie, erythropoiesis stimulating agents, lenalidomide, azacitidine or decitabine) early after diagnosis is associated with better outcomes than later initiation of drug therapy. For those patients who are eligible for allogeneic hematopoietic cell transplant and have a suitable donor, early transplant of lower-risk MDS is associated with worse outcomes compared to nontransplant approach, whereas early transplant therapy of higher-risk disease improves outcomes compared to delaying transplant. Here I review available data about MDS diagnostic patterns and early versus later diagnosis and therapy initiation.
Topics: Allografts; Azacitidine; Decitabine; Early Diagnosis; Hematinics; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Myelodysplastic Syndromes; Risk Factors
PubMed: 31779983
DOI: 10.1016/j.beha.2019.101099 -
International Journal of Nanomedicine 2019Acute myeloid leukemia mainly affects adult patients. Complete remission for patients younger than 60 years, who are candidates for standard induction therapy, is...
BACKGROUND
Acute myeloid leukemia mainly affects adult patients. Complete remission for patients younger than 60 years, who are candidates for standard induction therapy, is achieved in 60%-80% of cases. However, the prognosis is still poor for older patients, who are unfit for intensive chemotherapy, and only a few therapies are available. Hypomethylating agents, such as decitabine, are approved for such patients. The current dosing regimen consists of one administration per day, for 5 days, each 4 weeks.
METHODS
Here, we present the synthesis of a decitabine prodrug, combined with its encapsulation into a lipid-based nanocapsule formulation. Decitabine (C12) was synthetized, then loaded into nanocapsules. Its stability in phosphate buffer ans human plasma was checked. Its activity was evaluated by Cell proliferation assays and cell-cycle analysis on human erythroleukemia cells. Then its pharmacokinetics was determined on a rat model.
RESULTS
Decitabine (C12) was obtained with a yield of 50%. Drug loading into nanocarriers of 27.45±0.05 nm was 5.8±0.5 mg/mL. The stability of decitabine was improved and its activity on leukemia cells was not altered. Finally, pharmacokinetics studies showed a prolonged mean residence time of the drug.
CONCLUSION
Decitabine (C12) as a prodrug showed high encapsulation efficiency, a good stability in plasma with no impact on its activity on leukemia cells and improved pharmacokinetics.
Topics: Animals; Antimetabolites, Antineoplastic; Cell Cycle; Cell Proliferation; Decitabine; Drug Stability; Humans; Leukemia, Erythroblastic, Acute; Lipids; Male; Nanocapsules; Plasma; Rats; Rats, Wistar; Tissue Distribution; Tumor Cells, Cultured
PubMed: 30988610
DOI: 10.2147/IJN.S190482 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Oct 2022To investigate the efficacy and mechanism of decitabine maintenance therapy in patients with medium and low-risk acute myeloid leukemia(AML).
OBJECTIVE
To investigate the efficacy and mechanism of decitabine maintenance therapy in patients with medium and low-risk acute myeloid leukemia(AML).
METHODS
The newly diagnosed medium- and low-risk AML patients in the Second Affiliated Hospital of Anhui Medical University from December 2016 to December 2020 were retrospectively analyzed. Seventy-eight AML patients who were still in remission after consolidation treatment were divided into maintenance treatment group (31 cases) and control group (47 cases). The maintenance treatment patients received decitabine at 20 mg/m2 IV daily for 5 days, every three months for 6 cycles, the control group was only observed and tested regularly. Follow-up was completed by telephone or by viewing outpatient or inpatient medical records. Primary indicators were overall survival (OS), and secondary indicators include relapse-free survival (RFS), tolerance, cellular immune function and analysis of risk factors related to survival.
RESULTS
Median RFS in maintenance theatment and control groups was 30.1(26.2-33.8) months and 24.3(21.7-30.3) months (P=0.011), median OS 34.7(29.8-39.7) months and 27.7(24.1-31.3) months respectively(P=0.024), with a statistically significant difference. For the univariate and multivariate Cox regression analysis, only the minimal residual disease (HR=25.185, P<0.001) and the treatment methods (HR=0.124, P<0.001) affected the PFS and OS of patients. In the maintenance treatment group, CD3T cells, CD8T cells and NK cells increased significantly after decitabine maintenance treatment, and the regulatory T cells decreased significantly (P<0.05). Patients had a low incidence of grade 3-4 adverse events, hematological adverse events were mainly neutropenia and thrombocytopenia, non-hematological adverse events were mainly digestive tract symptoms, and the patient was well tolerated.
CONCLUSION
Maintenance treatment with decitabine provided benefit survival in patients with medium- and low-risk AML and is well tolerated. The mechanism may be inhibition the proliferation of regulatory T cells, induce and enhance the cytotoxic effect of CD8 T cells on tumor antigens.
Topics: Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; CD8-Positive T-Lymphocytes; Decitabine; Humans; Leukemia, Myeloid, Acute; Retrospective Studies; Treatment Outcome
PubMed: 36208237
DOI: 10.19746/j.cnki.issn.1009-2137.2022.05.011 -
Asian Pacific Journal of Cancer... Jun 2023Epigenetic changes such as histone deacetylation and DNA methylation play to regulate gene expression. DNA methylation plays a major role in cancer induction via...
UNLABELLED
Epigenetic changes such as histone deacetylation and DNA methylation play to regulate gene expression. DNA methylation plays a major role in cancer induction via transcriptional silencing of critical regulators such as tumor suppressor genes (TSGs). One approach to inhibit TSGs inactivation is to use chemical compounds, DNA methyltransferase inhibitors (DNMTIs). Previously, we investigated the effect of 5-aza-2'-deoxycytidine (5 AZA CdR or decitabine) on colon cancer and hepatocellular carcinoma cell lines. The present study aimed to investigate the effect of 5 AZA CdR on extrinsic (DR4, DR5, FAS, FAS-L, and TRAIL genes), intrinsic [pro- (Bax, Bak, and Bim) and anti- (Bcl-2, Bcl-xL, and Mcl-1) apoptotic genes], and JAK/STAT (SOCS1, SOCS3, JAK1, JAK2, STAT3, STAT5A, and STAT5B genes) pathways in neuroblastoma (IMR-32, SK-N-AS, UKF-NB-2, UKF-NB-3, and UKF-NB-4) and glioblastoma (SF-767, SF-763, A-172, U-87 MG, and U-251 MG) cell lines.
MATERIALS AND METHODS
The neuroblastoma and glioblastoma cells were cultured and treated with 5 AZA CdR. To determine cell viability, cell apoptosis, and the relative gene expression level, MTT assay, flow cytometry assay, and qRT-PCR were done respectively.
RESULTS
5 AZA CdR changed the expression level of the genes of the extrinsic, intrinsic, and JAK/STAT pathways by which induced cell apoptosis and inhibited cell growth in neuroblastoma and glioblastoma cell lines.
CONCLUSION
5 AZA CdR can play its role through extrinsic, intrinsic, and JAK/STAT pathways to induce cell apoptosis.
Topics: Humans; Decitabine; Janus Kinases; Glioblastoma; Signal Transduction; STAT Transcription Factors; Azacitidine; Cell Line; DNA Methylation; Neuroblastoma; Deoxycytidine; Cell Line, Tumor
PubMed: 37378911
DOI: 10.31557/APJCP.2023.24.6.1841 -
Frontiers in Immunology 2022DNA vaccines containing a fusion of the gene encoding chemokine MIP-3α (CCL20), the ligand for CCR6 on immature dendritic cells (DCs), to melanoma-associated antigen...
INTRODUCTION
DNA vaccines containing a fusion of the gene encoding chemokine MIP-3α (CCL20), the ligand for CCR6 on immature dendritic cells (DCs), to melanoma-associated antigen genes have enhanced anti-tumor immunity and efficacy compared to those lacking the chemokine gene. Previous work has shown that type-I interferon (IFNα or IFN) and 5-Aza-2'-deoxycytidine (5Aza) significantly enhance the therapeutic benefit of DNA vaccines as measured by reduced tumor burden and improved mouse survival.
METHODS
Here, we explored mouse intratumoral immune correlates underlying the therapeutic benefit of this combination regimen (vaccine, IFN, and 5Aza) as compared to vaccine alone and IFN and 5Aza without vaccine, focusing on chemokine mRNA expression by qRT-PCR and inflammatory cellular infiltration into the tumor microenvironment (TME) by flow cytometry and immunohistochemistry (IHC).
RESULTS
The combination group significantly upregulated intratumoral mRNA expression of key immune infiltration chemokines XCL1 and CXCL10. Flow cytometric analyses of tumor suspensions exhibited greater tumor infiltration of CD8+ DCs, CCR7+ DCs, and NK cells in the combination group, as well as reduced levels of myeloid-derived suppressor cells (MDSCs) in vaccinated groups. The mice receiving combination therapy also had greater proportions of effector/memory T-cells (Tem), in addition to showing an enhanced infiltration of Tem and central memory CD8+ T-cells, (Tcm). Tem and Tcm populations both correlated with smaller tumor size. Immunohistochemical analysis of tumors confirmed that CD8+ cells were more abundant overall and especially in the tumor parenchyma with combination therapy.
DISCUSSION
Efficient targeting of antigen to immature DCs with a chemokine-fusion vaccine offers a potential alternative approach to classic and dendritic cell-based vaccines. Combining this approach with IFNα and 5Aza treatments significantly improved vaccine efficacy. This treatment creates an environment of increased inflammatory chemokines that facilitates the trafficking of CD8+ DCs, NK cells, and CD8+ T-cells, especially memory cells, while reducing the number of MDSCs. Importantly, in the combination group, CD8+ cells were more able to penetrate the tumor mass in addition to being more numerous. Further analysis of the pathways engaged by our combination therapy is expected to provide additional insights into melanoma pathogenesis and facilitate the development of novel treatment strategies.
Topics: Animals; Mice; Decitabine; Interferon-alpha; Melanoma; RNA, Messenger; Tumor Microenvironment; Vaccines, DNA; Cancer Vaccines
PubMed: 36741387
DOI: 10.3389/fimmu.2022.1074644 -
Expert Review of Hematology 2023Cytarabine and anthracycline combination therapy (7 + 3 regimen) is the standard care for induction chemotherapy in adult patients with acute myeloid leukemia (AML).... (Review)
Review
INTRODUCTION
Cytarabine and anthracycline combination therapy (7 + 3 regimen) is the standard care for induction chemotherapy in adult patients with acute myeloid leukemia (AML). Although this intensive regimen achieves a high response rate, it is highly toxic, especially in elderly or frail patients. Hypomethylating agents approved initially for high-risk myelodysplastic syndrome had longer survival times than conventional care in elderly patients with newly diagnosed AML.
AREAS COVERED
We summarize the latest information regarding induction therapy using hypomethylating agents (azacitidine and decitabine) for newly diagnosed AML.
EXPERT OPINION
For untreated patients ineligible for an intensive regimen, a phase III trial exhibited the survival benefit of adding the highly selective BCL2 inhibitor venetoclax to azacitidine. The National Comprehensive Cancer Network guidelines recommend azacitidine or decitabine plus venetoclax as an option for patients with poor-risk AML, including those with mutations and AML with the cytogenetic features of myelodysplastic syndrome. Future studies should evaluate positioning this combination as an induction therapy for younger patients eligible for hematopoietic stem cell transplantation. Without randomized trials, propensity score matching analysis suggested a comparable prognosis between azacitidine combination and intensive chemotherapy. Considering the feasibility of a doublet regimen incorporating azacitidine, a triplet regimen should be examined.
Topics: Adult; Humans; Aged; Decitabine; Induction Chemotherapy; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Sulfonamides
PubMed: 37670667
DOI: 10.1080/17474086.2023.2256472 -
Blood Cancer Journal Jun 2023Treatment choice according to the individual conditions remains challenging, particularly in older patients with acute myeloid leukemia (AML) and high risk...
Treatment choice according to the individual conditions remains challenging, particularly in older patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). The impact of performance status, comorbidities, and physical functioning on survival is not well defined for patients treated with hypomethylating agents. Here we describe the impact of performance status (14% ECOG performance status 2), comorbidity (40% HCT-comorbidity index ≥ 2), and physical functioning (41% short physical performance battery < 9 and 17% ADL index < 6) on overall survival (OS) in 115 older patients (age ≥ 66 years) treated on a clinical trial with a 10-day decitabine schedule. None of the patient-related variables showed a significant association with OS. Multivariable analysis revealed that age > 76 years was significantly associated with reduced OS (HR 1.58; p = 0.043) and female sex was associated with superior OS (HR 0.62; p = 0.06). We further compared the genetic profiles of these subgroups. This revealed comparable mutational profiles in patients younger and older than 76 years, but, interestingly, revealed significantly more prevalent mutated ASXL1, STAG2, and U2AF1 in male compared to female patients. In this cohort of older patients treated with decitabine age and sex, but not comorbidities, physical functioning or cytogenetic risk were associated with overall survival.
Topics: Humans; Male; Female; Aged; Decitabine; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Mutation; Treatment Outcome
PubMed: 37336890
DOI: 10.1038/s41408-023-00850-6 -
Journal For Immunotherapy of Cancer Jan 2022The powerful 'graft versus leukemia' effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic cell transplantation in acute myeloid...
BACKGROUND
The powerful 'graft versus leukemia' effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic cell transplantation in acute myeloid leukemia (AML) provides rationale for investigation of immune-based therapies in this high-risk blood cancer. There is considerable preclinical evidence for potential synergy between PD-1 immune checkpoint blockade and the hypomethylating agents already commonly used for this disease.
METHODS
We report here the results of 17 H-0026 (PD-AML, NCT02996474), an investigator sponsored, single-institution, single-arm open-label 10-subject pilot study to test the feasibility of the first-in-human combination of pembrolizumab and decitabine in adult patients with refractory or relapsed AML (R-AML).
RESULTS
In this cohort of previously treated patients, this novel combination of anti-PD-1 and hypomethylating therapy was feasible and associated with a best response of stable disease or better in 6 of 10 patients. Considerable immunological changes were identified using T cell receptor β sequencing as well as single-cell immunophenotypic and RNA expression analyses on sorted CD3+ T cells in patients who developed immune-related adverse events (irAEs) during treatment. Clonal T cell expansions occurred at irAE onset; single-cell sequencing demonstrated that these expanded clones were predominately CD8+ effector memory T cells with high cell surface PD-1 expression and transcriptional profiles indicative of activation and cytotoxicity. In contrast, no such distinctive immune changes were detectable in those experiencing a measurable antileukemic response during treatment.
CONCLUSION
Addition of pembrolizumab to 10-day decitabine therapy was clinically feasible in patients with R-AML, with immunological changes from PD-1 blockade observed in patients experiencing irAEs.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Decitabine; Female; Humans; Immunotherapy; Leukemia, Myeloid, Acute; Male; Pilot Projects; Recurrence
PubMed: 35017151
DOI: 10.1136/jitc-2021-003392 -
NEJM Evidence Oct 2022BACKGROUND: The hypomethylating agents are part of the standard of care in the treatment of myelodysplastic syndromes (MDS), but their role in patients with lower-risk... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND: The hypomethylating agents are part of the standard of care in the treatment of myelodysplastic syndromes (MDS), but their role in patients with lower-risk disease is unclear. METHODS: We randomly assigned patients with previously untreated MDS with low/intermediate-1 risk by the International Prognostic Scoring System with a Bayesian response-adaptive design to receive either 20 mg/m2 decitabine daily or 75 mg/m2 azacitidine daily on days 1 to 3 every 28-day cycle. RESULTS: A total of 113 patients were treated: 73 (65%) with decitabine and 40 (35%) with azacitidine. The overall response rate was 67% and 48% in the decitabine and azacitidine groups, respectively (P=0.042); among 59 patients with baseline transfusion dependency, 19 (32%) reached transfusion independence (decitabine, 16 of 39 [41%]; azacitidine, 3 of 20 [15%]; P=0.039). Of the 19 patients who reached transfusion independence, the median duration of transfusion independency was 22 months. Among 54 patients who were transfusion independent at baseline, 5 patients (9%) became transfusion dependent after therapy. No early death was observed. With a median follow-up of 68 months, the median overall event-free survival and overall survival were 17 months and 33 months, respectively. CONCLUSIONS: Attenuated dose treatment of hypomethylating agents in patients with lower-risk MDS can improve outcomes without dose-limiting side effects in a high-risk cohort as defined by the Lower-Risk Prognostic Scoring System. (Funded in part by The University of Texas MD Anderson Cancer Center and others; ClinicalTrials.gov number, NCT01720225.)
Topics: Adult; Humans; Azacitidine; Decitabine; Myelodysplastic Syndromes; Treatment Outcome
PubMed: 38319837
DOI: 10.1056/EVIDoa2200034