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Cells Aug 2020Bladder cancer (BC) is the tenth most frequent cancer worldwide and is associated with high mortality when diagnosed in its most aggressive form, which is not reverted... (Review)
Review
Bladder cancer (BC) is the tenth most frequent cancer worldwide and is associated with high mortality when diagnosed in its most aggressive form, which is not reverted by the current treatment options. Thus, the development of new therapeutic strategies, either alternative or complementary to the current ones, is of major importance. The disruption of normal epigenetic mechanisms, namely, DNA methylation, is a known early event in cancer development. Consequently, DNA methyltransferase (DNMT) inhibitors constitute a promising therapeutic target for the treatment of BC. Although these inhibitors, mainly nucleoside analogues such as 5-azacytidine (5-aza) and decitabine (DAC), cause re-expression of tumor suppressor genes, inhibition of tumor cell growth, and increased apoptosis in BC experimental models and clinical trials, they also show important drawbacks that prevent their use as a valuable option for the treatment of BC. However, their combination with chemotherapy and/or immune-checkpoint inhibitors could aid in their implementation in the clinical practice. Here, we provide a comprehensive review of the studies exploring the effects of DNA methylation inhibition using DNMTs inhibitors in BC, from in vitro and in vivo studies to clinical trials.
Topics: Animals; Antimetabolites, Antineoplastic; Azacitidine; Cell Line, Tumor; DNA Methylation; Decitabine; Epigenesis, Genetic; Humans; Urinary Bladder Neoplasms
PubMed: 32784599
DOI: 10.3390/cells9081850 -
Clinical Epigenetics 2016Aberrant DNA methylation has been identified as a key molecular event regulating the pathogenesis of myelodysplastic syndromes (MDS); myeloid neoplasms with an inherent... (Comparative Study)
Comparative Study Review
BACKGROUND
Aberrant DNA methylation has been identified as a key molecular event regulating the pathogenesis of myelodysplastic syndromes (MDS); myeloid neoplasms with an inherent risk of transformation to acute myeloid leukemia (AML). Based on the above findings, DNA hypomethylating agents (HMA) have been widely used to treat AML and MDS, especially in elderly patients and in those who are not eligible for allogeneic stem cell transplantation (SCT). Our goal was to determine if there is any therapeutic advantage of HMA vs. conventional care regimens (CCR) and indirectly compare the efficacy of azacitidine and decitabine in this patient population.
METHODS
Eligible studies were limited to randomized controlled trials comparing HMA to CCR in adult patients with AML or MDS.
RESULTS
Overall survival (OS) rate was 33.2 vs. 21.4 % (RR 0.83, 95 % CI 0.71-0.98) and overall response rate (ORR) 23.7 vs. 13.4 % (RR 0.87, 95 % CI 0.81-0.93) for HMA and CCR, respectively. In subgroup analyses, only azacitidine treatment showed OS improvement (RR 0.75, 95 % CI 0.64-0.98) and not decitabine. Cytogenetic risk or bone marrow blast count did not have independent prognostic impact.
CONCLUSION
Collectively, these results demonstrate that HMA have superior outcomes compared to CCR and suggest that azacitidine in comparison to decitabine, may be more effective.
Topics: Aged; Antimetabolites, Antineoplastic; Azacitidine; DNA Methylation; Decitabine; Epigenesis, Genetic; Female; Humans; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Prognosis; Randomized Controlled Trials as Topic; Survival Rate; Treatment Outcome
PubMed: 27307795
DOI: 10.1186/s13148-016-0233-2 -
The Oncologist 2013The introduction of the hypomethylating agents azacitidine and decitabine has been a major advancement in the treatment of patients with higher-risk myelodysplastic...
The introduction of the hypomethylating agents azacitidine and decitabine has been a major advancement in the treatment of patients with higher-risk myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia who are ineligible for more intensive treatments. This concise drug review summarizes the current state of treatment with azacitidine and decitabine.
Topics: Antimetabolites, Antineoplastic; Azacitidine; Clinical Trials, Phase III as Topic; Decitabine; Drug Approval; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes
PubMed: 23671007
DOI: 10.1634/theoncologist.2012-0465 -
The Oncologist Mar 2005On May 19, 2004, azacitidine (5-azacytidine; Vidaza(trade mark); Pharmion Corporation, Boulder, CO, http://www.pharmion.com) for injectable suspension received regular... (Review)
Review
On May 19, 2004, azacitidine (5-azacytidine; Vidaza(trade mark); Pharmion Corporation, Boulder, CO, http://www.pharmion.com) for injectable suspension received regular approval by the U.S. Food and Drug Administration (FDA) for the treatment of all subtypes of myelodysplastic syndrome (MDS). This report summarizes the basis for this approval. Effectiveness was demonstrated in one randomized, controlled trial comparing azacitidine administered s.c. with best supportive care (observation group) and in two single-arm studies, one in which azacitidine was administered s.c. and in the other in which it was administered i.v. The dose of azacitidine, 75 mg/m2/day for 7 days every 28 days, was the same in all three studies. In the randomized trial, study participants were well matched with respect to age, sex, race, performance status, MDS subtype, and use of transfusion during the 3 months before study entry. Patients in the observation arm were permitted by protocol to cross over to azacitidine treatment if their disease progressed according to prespecified criteria. During the course of the study, more than half of the patients in the observation arm did cross over to the azacitidine treatment arm. The primary efficacy end point was the overall response rate. Response consisted of complete or partial normalization of blood cell counts and of bone marrow morphology. The response rate in the azacitidine arm was about 16%; there were no responses in the observation arm. The response rates in the two single-arm studies were similar (13% and 19%). The responses were sustained, with median durations of 11 months and 17 months respectively. Responding patients who were transfusion dependent at study entry lost the need for transfusions. In addition, about 19% of patients had less than partial responses (termed improvement), and two-thirds of them became transfusion independent. Common adverse events associated with azacitidine treatment were gastrointestinal (nausea, vomiting, diarrhea, constipation, and anorexia), hematologic (neutropenia, thrombocytopenia), fevers, rigors, ecchymoses, petechiae, injection site events, arthralgia, headache, and dizziness. Liver function abnormalities occurred in 16% of patients with intercurrent hepatobiliary disorders and in two patients with previously diagnosed liver cirrhosis. Renal failure occurred in patients during sepsis and hypotension. There were no deaths attributed to azacitidine. Azacitidine, the first drug approved by the U.S. FDA for MDS, has a favorable safety profile and provides a clinical benefit of eliminating transfusion dependence and complete or partial normalization of blood counts and bone marrow blast percentages in responding patients.
Topics: Adolescent; Adult; Aged; Antimetabolites, Antineoplastic; Azacitidine; Blood Transfusion; Drug Approval; Female; Humans; Infusions, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Myelodysplastic Syndromes; Randomized Controlled Trials as Topic; Treatment Outcome; United States; United States Food and Drug Administration
PubMed: 15793220
DOI: 10.1634/theoncologist.10-3-176 -
Medical Science Monitor : International... Jan 2021BACKGROUND Hypomethylating agents (HMA) are considered the first-line therapy for high-risk myelodysplastic syndromes (MDS). However, as the efficacy and safety of...
BACKGROUND Hypomethylating agents (HMA) are considered the first-line therapy for high-risk myelodysplastic syndromes (MDS). However, as the efficacy and safety of rational dosing regimens are lacking, we evaluated the effectiveness and safety of reduced-dose azacitidine (AZA) vs. decitabine (DAC) in adult MDS patients. MATERIAL AND METHODS This retrospective study was conducted at the Institute of Hematology & Blood Diseases Hospital, for hospitalized MDS patients diagnosed (WHO 2008 classification criteria) from May 2006 to February 2020. These AZA- and DCA-naive patients treated with AZA 100 mg/(m²·day) for 5 days to 7 days or DAC 20 mg/(m²·day) for 3 days to 4 days, or 20 mg/(m²·day) 1 day/week for 3 weeks/month were assessed for treatment responses and adverse events. RESULTS Of the 158 enrolled MDS patients, 120 and 38 patients were administered reduced-dose DAC and AZA, respectively. All the patients received a median of 2 treatment cycles. The overall response rates (ORR) were 50.0% and 73.3% in the AZA and DAC groups, respectively (P=0.007). The percentage of platelet transfusion dependence in the AZA group was lower than the DAC group (P=0.026). The multivariate analysis demonstrated that the DAC treatment was a significant factor for improved responses (OR 2.928; 95% CI 1.267-6.896; P=0.012), and the absolute neutrophil count (ANC) was a predictor of the ORR (OR 0.725; 95% CI 0.558-0.898; P=0.008). Neutropenia (P=0.016) and infection (P=0.032) incidences were higher in the DAC group. CONCLUSIONS The reduced-dose DAC group demonstrated a better response than the AZA group in MDS patients with different prognostic risks. The patients' pre-treatment ANC was a significant factor associated with the ORR.
Topics: Aged; Azacitidine; China; Decitabine; Dose-Response Relationship, Drug; Drug Tapering; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Retrospective Studies; Treatment Outcome
PubMed: 33514682
DOI: 10.12659/MSM.928454 -
Cancer Nov 2005Tumor cell proliferation, de-differentiation, and progression depend on a complex combination of altered cell cycle regulation, excessive growth factor pathway... (Review)
Review
Tumor cell proliferation, de-differentiation, and progression depend on a complex combination of altered cell cycle regulation, excessive growth factor pathway activation, and decreased apoptosis. The understanding of these complex mechanisms should lead to the identification of potential molecular markers, targets, and molecular profiles that should eventually expand and improve therapeutic intervention. It now appears clear that methylation plays a central role in transformation, both in vitro and in vivo. However, the exact targets and mechanism(s) are not yet fully understood. This is partly due to the significant number of genes altered by changes in intracellular methyltransferase activity and the chemical agents used to modulate gene expression. The complex nature of methylation's role in regulating gene expression suggests that in addition to investigating individual genes, researchers should develop more comprehensive methods to examine gene expression patterns and their predictive value as this will likely be necessary in the future. If methylation plays a role in transformation, then it seems logical that genes regulating intracellular methylation status may be used as molecular markers to profile tumors by any new methods currently being developed. Perhaps more noteworthy is that DNMT genes may be found to be novel molecular targets for new factor-specific anticancer agents. This idea will be addressed.
Topics: Azacitidine; Biomarkers, Tumor; Cell Cycle; Cell Transformation, Neoplastic; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; Decitabine; Drug Resistance, Neoplasm; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Protein Processing, Post-Translational; DNA Methyltransferase 3B
PubMed: 16149092
DOI: 10.1002/cncr.21395 -
Pharmacology & Therapeutics Aug 2018DNA methylation plays a pivotal role in the etiology of cancer by mediating epigenetic silencing of cancer-related genes. Since the relationship between aberrant DNA... (Review)
Review
DNA methylation plays a pivotal role in the etiology of cancer by mediating epigenetic silencing of cancer-related genes. Since the relationship between aberrant DNA methylation and cancer has been understood, there has been an explosion of research at developing anti-cancer therapies that work by inhibiting DNA methylation. From the discovery of first DNA hypomethylating drugs in the 1980s to recently discovered second generation pro-drugs, exceedingly large number of studies have been published that describe the DNA hypomethylation-based anti-neoplastic action of these drugs in various stages of the pre-clinical investigation and advanced stages of clinical development. This review is a comprehensive report of the literature published in past 40 years, on so far discovered nucleosidic DNA methylation inhibitors in chronological order. The review will provide a complete insight to the readers about the mechanisms of action, efficacy to demethylate and re-express various cancer-related genes, anti-tumor activity, cytotoxicity profile, stability, and bioavailability of these drugs. The review further presents the far known mechanisms of primary and secondary resistance to azanucleoside drugs. Finally, the review highlights the ubiquitous role of DNA hypomethylating epi-drugs as chemosensitizers and/or priming agents, and recapitulate the combinatorial cancer preventive effects of these drugs with other epigenetic agents, conventional chemo-drugs, or immunotherapies. This comprehensive review analyzes the beneficial characteristics and drawbacks of nucleosidic DNA methylation inhibitors, which will assist the pre-clinical and clinical researchers in the design of future experiments to improve the therapeutic efficacy of these drugs and circumvent the challenges in the path of successful epigenetic therapy.
Topics: Animals; Antineoplastic Agents; Azacitidine; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; Drug Discovery; Drug Resistance, Neoplasm; Humans; Nucleosides; Thioguanine
PubMed: 29454856
DOI: 10.1016/j.pharmthera.2018.02.006 -
Clinical Epigenetics Feb 2023miRNAs are small non-coding RNAs that regulate gene expression and are linked to cancer development and progression. miRNA profiles are currently studied as new...
BACKGROUND
miRNAs are small non-coding RNAs that regulate gene expression and are linked to cancer development and progression. miRNA profiles are currently studied as new prognostic factors or therapeutic perspectives. Among hematological cancers, myelodysplastic syndromes at higher risk of evolution into acute myeloid leukemia are treated with hypomethylating agents, like azacitidine, alone or in combination with other drugs, such as lenalidomide. Recent data showed that, during azacitidine and lenalidomide therapy, the concurrent acquisition of specific point mutations affecting inositide signalling pathways is associated with lack or loss of response to therapy. As these molecules are implicated in epigenetic processes, possibly involving miRNA regulation, and in leukemic progression, through the regulation of proliferation, differentiation and apoptosis, here we performed a new miRNA expression analysis of 26 high-risk patients with myelodysplastic syndromes treated with azacitidine and lenalidomide at baseline and during therapy. miRNA array data were processed, and bioinformatic results were correlated with clinical outcome to investigate the translational relevance of selected miRNAs, while the relationship between selected miRNAs and specific molecules was experimentally tested and proven.
RESULTS
Patients' overall response rate was 76.9% (20/26 cases): complete remission (5/26, 19.2%), partial remission (1/26, 3.8%), marrow complete remission (2/26, 7.7%), hematologic improvement (6/26, 23.1%), hematologic improvement with marrow complete remission (6/26, 23.1%), whereas 6/26 patients (23.1%) had a stable disease. miRNA paired analysis showed a statistically significant up-regulation of miR-192-5p after 4 cycles of therapy (vs baseline), that was confirmed by real-time PCR analyses, along with an involvement of BCL2, that was proven to be a miR-192-5p target in hematopoietic cells by luciferase assays. Furthermore, Kaplan-Meier analyses showed a significant correlation between high levels of miR-192-5p after 4 cycles of therapy and overall survival or leukemia-free survival, that was stronger in responders, as compared with patients early losing response and non-responders.
CONCLUSIONS
This study shows that high levels of miR-192-5p are associated with higher overall survival and leukemia-free survival in myelodysplastic syndromes responding to azacitidine and lenalidomide. Moreover, miR-192-5p specifically targets and inhibits BCL2, possibly regulating proliferation and apoptosis and leading to the identification of new therapeutic targets.
Topics: Humans; Azacitidine; Lenalidomide; MicroRNAs; DNA Methylation; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Proto-Oncogene Proteins c-bcl-2
PubMed: 36803590
DOI: 10.1186/s13148-023-01441-9 -
Oncotarget Feb 2017Two hypomethylating agents (HMAs), azacitidine and decitabine, have demonstrated clinical activities in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML);...
Two hypomethylating agents (HMAs), azacitidine and decitabine, have demonstrated clinical activities in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML); however, potential problems include development of acquired resistance. HMA-resistant patients have very poor prognosis and this cohort of patients constitutes an important area of research. To understand the mechanisms underlying HMA-resistance and to overcome it, we established an azacitidine-resistant cell line, MOLM/AZA-1 and a decitabine-resistant cell line, MOLM/DEC-5 using MOLM-13. For cytogenetic characterization, we performed microarray-based comparative genomic hybridization (array-CGH), which identified a total of 15 copy number alterations (CNAs). Among these CNAs, eight regions in HMA-resistant cell lines showed CNA patterns distinct from the parental MOLM-13 genome. Single nucleotide polymorphism (SNP) microarray was also performed to obtain a more reliable interpretation of the identified CNAs, and all HMA-resistance-specific CNAs except one detected by array-CGH were successfully validated. In addition to CNAs, copy neutral loss of heterozygosity and mosaic loss events were identified in HMA-resistant cell lines. In our resistant cell lines, MDR-1 was not overexpressed, while DNMT3b was upregulated. Azacitidine and decitabine did not inhibit DNMT1, DNMT3a, or DNMT3b in both HMA-resistant cell lines, while they inhibited the enzymes in parental MOLM-13. We also developed mouse xenograft models using MOLM/AZA-1 and MOLM/DEC-5. Our in vitro and in vivo models of HMA-resistant cell lines will provide clues for the elucidation of molecular mechanisms related to the development of resistance to HMA and tools for the application of novel therapeutics for AML and MDS.
Topics: Azacitidine; Cell Line, Tumor; Cytogenetics; DNA Methylation; Decitabine; Humans; Leukemia, Myeloid, Acute; Prognosis
PubMed: 28052028
DOI: 10.18632/oncotarget.14342 -
American Journal of Hematology Feb 2023
Topics: Humans; Myelodysplastic Syndromes; Azacitidine; Sulfonamides; Bridged Bicyclo Compounds, Heterocyclic
PubMed: 36377194
DOI: 10.1002/ajh.26781