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Allen S Yang - One of the best experts on this subject based on the ideXlab platform.
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2 deoxy n4 2 4 nitrophenyl ethoxycarbonyl 5 azacytidine a novel inhibitor of dna methyltransferase that requires activation by human carboxylesterase 1
Cancer Letters, 2008Co-Authors: Hyangmin Byun, Si Ho Choi, Peter W Laird, Maqbool A Siddiqui, Victor E Marquez, Binh N Trinh, Allen S YangAbstract:2’-Deoxy-N4-[2-(4-nitrophenyl) ethoxycarbonyl]-5-azacytidine (NPEOC-DAC), decitabine with a modification of the N4 position of the Azacitidine ring can be used to inhibit DNA methyltransferase. This modification protects the Azacitidine ring and can be cleaved by carboxylesterase to release decitabine. NPEOC-DAC was 23-fold less potent at low doses (<10 µM) than decitabine at inhibiting DNA methylation, and was also associated with a 3-day delay in its effect. However, at doses ≥ 10 µM NPEOC-DAC was more effective at inhibiting DNA methylation. Theses differences between decitabine and NPEOC-DAC are dependent on the cleavage of the carboxylester bond, and could be potentially exploited pharmacologically.
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2 deoxy n4 2 4 nitrophenyl ethoxycarbonyl 5 azacytidine a novel inhibitor of dna methyltransferase that requires activation by human carboxylesterase 1
Cancer Letters, 2008Co-Authors: Hyangmin Byun, Si Ho Choi, Peter W Laird, B Trinh, Maqbool A Siddiqui, Victor E Marquez, Allen S YangAbstract:2'-Deoxy-N4-[2-(4-nitrophenyl)ethoxycarbonyl]-5-azacytidine (NPEOC-DAC), decitabine with a modification of the N4 position of the Azacitidine ring can be used to inhibit DNA methyltransferase. This modification protects the Azacitidine ring and can be cleaved by carboxylesterase to release decitabine. NPEOC-DAC was 23-fold less potent at low doses ( or = 10microM NPEOC-DAC was more effective at inhibiting DNA methylation. Theses differences between decitabine and NPEOC-DAC are dependent on the cleavage of the carboxylester bond, and could be potentially exploited pharmacologically.
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phase i ii study of mgcd0103 an oral isotype selective histone deacetylase hdac inhibitor in combination with 5 Azacitidine in higher risk myelodysplastic syndrome mds and acute myelogenous leukemia aml
Blood, 2007Co-Authors: Guillermo Garciamanero, Allen S Yang, Virginia M Klimek, Jorge E Cortes, Farhad Ravandi, Willie Newsome, Julie Dumouchel, Marja Dubay, Christiane Maroun, Eric LailleAbstract:Epigenetic alterations are common in leukemia. MGCD0103 in an oral isotype-selective HDAC inhibitor that synergizes in vitro with the DNA methyltransferase inhibitor 5-Azacitidine (Vidaza, Pharmion). Both agents have single-agent clinical activity in MDS and AML (Garcia-Manero, ASCO, 2006 & Silverman, JCO, 2002). We have developed a Phase I/II study of 5-Azacitidine in combination with MGCD0103 in patients with AML and MDS. Patients with MDS (≥10% marrow blasts), relapsed/refractory AML, or untreated elderly patients with AML were eligible. Adequate performance status, renal and hepatic functions were required. 5-Azacitidine was administered at its approved dose/schedule: 75 mg/m2 SC daily for the first 7 days of a 28 day cycle. MGCD0103 was administered as a flat dose orally three-times a week starting on the 5th day of 5-Azacitidine administration. The phase I portion of the study design followed a classic “3+3” model and only MGCD0103 was dose escalated. The phase II portion targeted a 30% response rate. Final data from the Phase I and II portions of the study will be presented at the Meeting. Five dose levels of MGCD0103 have been evaluated: 35, 60, 90, 110 and 135 mg. At current data cut-off, 37 patients registered in the study were fully evaluable: median age was 67 (range 27–85); 31 patients had AML and 6 MDS. A total of 97 cycles were administered to date, mean = 2.6 (range 1–12). Dose limiting toxicities included nausea, vomiting, anorexia, diarrhea and dehydration which appear similar to dose limiting toxicities for MGCD0103 alone. The MTD of MGCD0103 was initially determined to be 110 mg, however, upon cohort expansion, this dose level was associated with excess toxicity and the starting dose was decreased to 90 mg. Eleven (30%) patients have achieved response: 4 CR, 5 CR-i, and 2 PR. Of these 11 patients, 6 continue on study with mean duration on study of 7 cycles. Of the 5 patients discontinued, 3 discontinued due to SAEs, 1 due to progressive disease and 1 to undergo transplantation. Of the 27 patients at the phase II dose levels of 90 and 110mg, 10 achieved a response (37%; same rate at both doses). Preliminary response data are available at the time of abstract preparation for 13 additional patients, revealing 4 with CR (one of which had 1% residual peripheral blast) and 3 with CR-I for a response rate of 53% in this subset. MGCD0103 pharmacokinetics were not affected by 5-Azacitidine. Likewise, co-administration of MGCD0103 had no impact on the pharmacokinetics of 5-Azacitidine. A majority of patients exhibited a substantial reduction in PBMC HDAC activity during treatment with the combination. Analysis of DNA methylation is ongoing. In conclusion, the combination of 5-Azacitidine with MGCD0103 is safe in patients with advanced AML/MDS and has clinical activity potentially superior to that expected with 5-Azacitidine alone in this patient population. These results form the bases of a planned randomized study of 5-Azacitidine with or without MGCD0103 in AML and MDS.
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hydroxycarbamide in combination with Azacitidine or decitabine is antagonistic on dna methylation inhibition
British Journal of Haematology, 2007Co-Authors: Si Ho Choi, Hyangmin Byun, Jennifer M Kwan, Jean Pierre J Issa, Allen S YangAbstract:Azacitidine and decitabine are cytidine analogues that inhibit DNA methylation, and are used to treat myeloid haematological malignancies. Hydroxycarbamide (HC) (also known as hydroxyurea), a ribonucleotide reductase (RR) inhibitor, blocks the conversion of ribonucleotides to deoxyribonucleotides, and is also used to treat leukaemia and sickle-cell disease. Azacitidine is a ribonucleoside and decitabine is a deoxyribonucleoside; therefore, we hypothesized that inhibition of RR by HC would be antagonistic to Azacitidine and synergistic to decitabine. HL-60 and T24 cancer cell lines were treated with Azacitidine or decitabine in combination with HC and DNA methylation of LRE1, MAGEA1 and CDKN2A was quantitatively measured by bisulphite-polymerase chain reaction pyrosequencing. Surprisingly, we found that HC blocked the ability of both Azacitidine and decitabine to inhibit DNA methylation and this antagonistic effect was attributable to the arrest of the cell cycle induced by HC. However, this antagonism could be avoided with sequential treatment of HC followed by Azacitidine or decitabine. This data suggest that concurrent combination of HC blocks the ability of Azacitidine and decitabine to inhibit DNA methylation and therefore these drugs should be used sequentially.
Guillermo Garciamanero - One of the best experts on this subject based on the ideXlab platform.
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a systematic review of higher risk myelodysplastic syndromes clinical trials to determine the benchmark of Azacitidine and explore alternative endpoints for overall survival
Leukemia Research, 2021Co-Authors: Jacqueline S Garcia, Guillermo Garciamanero, Ronan T Swords, Gail J Roboz, Meagan A Jacoby, Wan Jen Hong, Xiaoqing Yang, Ying Zhou, Uwe Platzbecker, David P SteensmaAbstract:The hypomethylating agent Azacitidine can prolong overall survival (OS) in patients with higher risk-myelodysplastic syndromes (HR-MDS) compared to conventional regimens. However, outcomes differ largely between studies, making it challenging to determine the contribution of novel therapies added to Azacitidine. Further, a discrepancy is seen between complete (CR) or partial (PR) response rates and OS improvement with Azacitidine, making it challenging to rely on earlier endpoints than OS. We conducted a systematic literature search and study-level systematic review of 237 clinical studies to better understand outcomes for HR-MDS patients treated with Azacitidine. Pooled marrow CR was 9% (N = 2654; 95% CI: 6-13 %), CR rate was 17 % (N = 6943; 95% CI: 15-20 %), and median OS (mOS) was 18.6 months (N = 2820; 95% CI: 15.3-21.9). A weak correlation to mOS was detected with CR rate (207 patient cohorts, Pearson's r = 0.315; P < 0.0005), and a much stronger correlation with median progression-free survival (mPFS) (r=0.88, P = 3 × 10-14). Six-months progression-free survival rates correlated with 1-year OS rates but were only infrequently reported (N = 41 patient cohorts) therefore not allowing a robust recommendation for a surrogate to the established OS endpoint. Larger patient numbers and patient-level data appear necessary, especially for designing future clinical trials using Azacitidine combinations.
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phase 1 dose escalation trial of ilorasertib a dual aurora vegf receptor kinase inhibitor in patients with hematologic malignancies
Investigational New Drugs, 2015Co-Authors: Guillermo Garciamanero, Tapan M Kadia, Hagop M Kantarjian, Raoul Tibes, Martha Arellano, Emily A Knight, Hao Xiong, Qin Qin, Wijith Munasinghe, Lisa RobertsrappAbstract:Background Ilorasertib (ABT-348) is a novel inhibitor of Aurora kinase, vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptors, and the Src families of tyrosine kinases. Ilorasertib alone or in combination with Azacitidine demonstrated activity in preclinical models in various hematological malignancies, indicating that pan-Aurora kinase and multiple kinase inhibition may have preferential antileukemic activity. This phase 1 trial determined the safety, pharmacokinetics, and preliminary antitumor activity of ilorasertib alone or combined with Azacitidine in advanced hematologic malignancies. Patients and methods Fifty-two patients (median age, 67 years; 35 % with >4 prior regimens) with acute myelogenous leukaemia (AML; n = 38), myelodysplastic syndrome (n = 12), or chronic myelomonocytic leukaemia (n = 2) received 3 or 6 doses of ilorasertib per 28-day cycle and were assigned to arm A (once-weekly oral), B (twice-weekly oral), C (once-weekly oral plus Azacitidine), or D (once-weekly intravenous) treatment. Results Maximum tolerated doses were not determined; the recommended phase 2 oral monotherapy doses were 540 mg once weekly and 480 mg twice weekly. The most common grade 3/4 adverse events were hypertension (28.8 %), hypokalemia (15.4 %), anemia (13.5 %), and hypophosphatemia (11.5 %). Oral ilorasertib pharmacokinetics appeared dose proportional, with a 15-hour half-life and no interaction with Azacitidine. Ilorasertib inhibited biomarkers for Aurora kinase and VEGF receptors, and demonstrated clinical responses in 3 AML patients. Conclusions Ilorasertib exhibited acceptable safety and pharmacokinetics at or below the recommended phase 2 dose, displayed evidence of dual Aurora kinase and VEGF receptor kinase inhibition, and activity in AML.
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interaction between myelomonocytic and lymphoid cells in a patient with acute myelomonocytic leukemia and chronic lymphocytic leukemia
Leukemia & Lymphoma, 2014Co-Authors: Paolo Strati, Guillermo Garciamanero, John T Manning, Zeev EstrovAbstract:A sixty-five year old Hispanic male presented to his local clinic in September 2012 with a new-onset fatigue. On physical examination his liver could be palpated 2 cm and his spleen 3 cm below the costal margins. His hemoglobin level was 10 g/dl and his leukocyte count was 12,000 X 106/ml with 5,200 X 106/ml monocytes. A bone marrow aspiration and biopsy were compatible with chronic myelomonocytic leukemia type 1 (CMML-1). Scattered clusters of small PAX5-positive B-cells and an interstitial infiltrate of CD3-positive T-cells were noted and a cytogenetic analysis revealed an 11q23-25 deletion in 2 metaphases. Polymerase chain reaction (PCR) analysis did not detect BCR-ABL1 transcripts or abnormalities in PDGFRA and PDGFRB. The patient was treated with Azacitidine 100 mg intravenously daily, for 7 consecutive days once a month. Despite two cycles of therapy, the patient remained transfusion-dependent and his leucocyte count rose to 86,000 X 106/ml with 53,000 X 106/ml monocytes and 32,000 X 106/ml lymphocytes. Nevertheless, a third cycle of Azacitidine was administered and the patient was referred to our institution. A repeat bone marrow aspiration detected 20% monoblasts (Figure 1A, right lower corner) expressing CD11c antigen as assessed by immunohistochemistry (Figure 1D) and 24% monocytes. Flow cytometry analysis detected a large population of cells co-expressing CD45 (dim), CD13, CD15 (partial), CD33, CD4 (dim), CD36 (partial), CD38, CD64 partial, CD117, CD123, MPO, and HLA-DR. Together, these findings were consistent acute myelomonocytic leukemia (AMML), likely transformed from CMML. In addition, a large population of mature small lymphocytes (Figure 1A, left upper corner) co-expressing CD5 (Figure 1B) and CD19 (Figure 1C) antigens was noted. Flow cytometry analysis showed that 15% percent of the total events were those of cells co-expressing CD5 (dim), CD19+, CD20 (dim), CD22, CD23, CD43, CD200 (dim), IgG lambda, but not FMC-7, or CD11c antigens, consistent with a concomitant diagnosis of CLL. Unluckily, as more emphasis was given to the former diagnosis, no prognostic analysis, including Fluorescence In Situ Hybridization and immunoglobulin heavy-chain (IgH) gene rearrangement were performed. Polymerase chain reaction (PCR) analysis revealed FLT3 internal tandem duplication (ITD) with an ITD ratio of 0.221 (a D835 point mutation was not detected). Azacitidine was continued at the same dose and schedule and sorafenib 400 mg twice daily was added. After 1 month of treatment, the patient developed a grade 3-4 anemia and neutropenia and therefore the sorafenib dose was reduced to 200 mg twice daily. No toxicities other than hematological toxicity were noted. After 3 cycles of therapy, the patient’s liver and spleen shrunk and were no longer detected below costal margins and he became transfusion-independent. His hemoglobin level was 10 g/dl, his white blood cell count was 5,900 X 106/ml with no blasts and a normal number of monocytes and lymphocytes in the peripheral blood smear, and his platelet count was 60,000 X 106/ml. A bone marrow aspiration and biopsy showed only 11% myelo-monoblasts and 36% monocytes, compatible with CMML. CLL cell aggregates were no longer detected by morphologic analysis (Figure 1E). Continuation of the same treatment regimen was recommended. At 6 months, the patient was transfusion-independent and his physical exam was normal. His hemoglobin level was 10.1 g/dl, platelet count was 115 X 106/ml, and white blood cells were 2,500 X 106/ml with no blasts and a normal number of monocytes and lymphocytes in the peripheral blood smear. However, a bone marrow aspiration and biopsy was compatible with relapsed AMML with 33% myelo-monoblasts and, in addition, relapsed CLL, interstitial pattern, comprising 5-10% of the total bone marrow cellularity (Figure 1F). PCR analysis detected for the first time a FLT3 D835 mutation (ratio 0.274). Figure 1 A. Bone marrow clot section shows immature cells with monoblastic morphology (right lower corner) intermixed with mature-appearing lymphocyte (left upper corner), H & E, X40. B and C. The mature-appearing lymphocytes co-express CD5 and CD19, consistent ... Several studies established that the microenvironment provides Chronic Lymphocitic Leukemia (CLL) cells with proliferation signals and survival advantage1. An important component of the CLL cell microenvironment consists of monocyte-derived cells. Like solid tumor-associated macrophages2, stromal monocyte-derived nurse-like cells maintain and protect CLL cells. Here we present a patient with myelomonocytic leukemia and CLL in whom the expansion of the CLL clone depended on the presence of neoplastic monocytes. The clinical activity of B-cell receptor signal transduction inhibitors3 raised the possibility that other kinase inhibitors might provide clinical benefits in patients with CLL. Sorafenib is a multi-kinase inhibitor used in various solid tumors. In vitro studies suggested that sorafenib might be active in CLL as it induced apoptosis in primary CLL cells by downregulation of the anti-apoptotic proteins Bcl-2 and Mcl-14, 5. The patient described in this report had both myelomonocytic leukemia and CLL. Whereas the myelomonocytic clone was likely resistant to azacytidine, as progression from CMML to AMML occurred during treatment with azacytidine, it was sensitive to sorafenib, administered because FLT-3 ITD was detected. At the same time the CLL clone, expanded during the myelomonocytic disease progression, diminished when the AMML clone was suppressed. It is unlikely that azacytidine eradicated the CLL clone as it expanded during Azacitidine treatment, consistent with clinical data showing that Azacitidine had no clinical activity in fludarabine-refractory CLL6. It is also unlikely that sorafenib directly suppressed the CLL clone, as the above mentioned in vitro studies would suggest. In fact, the CLL clone re-surfaced when the AMML clone was no longer responsive to treatment. It is not reasonable that both clones became resistant at the same time. The possibility that both the myelomonocytic and the CLL cells arose from the same hematopoietic clone seems doubtful as FLT-3 mutations have never been detected in CLL. A last possibility is an incidental coexistence and a spontaneous regression of the CLL clone, as previously described7, 8. However, its symmetrical parallelism with the AMML clone points toward this hypothesis. Recent studies confirm the important role monocytes and monocyte-derived cells such as NLCs play in the pathobiology of CLL as an increased numbers of circulating monocytes and monocyte-derived factors were found to be associated with an unfavorable outcome in patients with CLL9, 10. Therefore, it is very likely that in our patient myelomonocytic leukemia cells functioned as NLCs and stimulated the expansion of CLL clone.
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phase i study of oral Azacitidine in myelodysplastic syndromes chronic myelomonocytic leukemia and acute myeloid leukemia
Journal of Clinical Oncology, 2011Co-Authors: Guillermo Garciamanero, Steven D Gore, Eric Laille, Christopher R Cogle, Renee Ward, Tao Shi, Kyle J Macbeth, Heidi Giordano, Sarah Sakoian, Elias J JabbourAbstract:Purpose To determine the maximum-tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and clinical activity of an oral formulation of Azacitidine in patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). Patients and Methods Patients received 1 cycle of subcutaneous (SC) Azacitidine (75 mg/m2) on the first 7 days of cycle 1, followed by oral Azacitidine daily (120 to 600 mg) on the first 7 days of each additional 28-day cycle. Pharmacokinetic and pharmacodynamic profiles were evaluated during cycles 1 and 2. Adverse events and hematologic responses were recorded. Cross-over to SC Azacitidine was permitted for nonresponders who received ≥ 6 cycles of oral Azacitidine. Results Overall, 41 patients received SC and oral Azacitidine (MDSs, n = 29; CMML, n = 4; AML, n = 8). Dose-limiting toxicity (grade 3/4 diarrhea) occurred at the 600-mg dose and MTD was 480 mg. Most common grade 3/4 adverse events were diarrhea (12.2%), ...
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maintenance therapy with low dose Azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome a dose and schedule finding study
Cancer, 2010Co-Authors: Marcos Lima, Leandro De Padua Silva, Hoang Q Nguyen, Roy B. Jones, Peter F Thall, Sergio Giralt, Krishna V Komanduri, Richard E. Champlin, Thomas M Braun, Guillermo GarciamaneroAbstract:BACKGROUND: Recurrence is a major cause of treatment failure after allogeneic transplantation for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), and treatment options are very limited. Azacitidine is a DNA methyltransferase inhibitor with activity in myeloid disease. The authors hypothesized that low-dose Azacitidine administered after transplant would reduce recurrence rates, and conducted a study to determine a safe dose/schedule combination. METHODS: Forty-five high-risk patients were treated. Median age was 60 years; median number of comorbidities was 3; 67% were not in remission. By using a Bayesian adaptive method to determine the best dose/schedule combination based on time to toxicity, the authors investigated combinations of 5 daily Azacitidine doses, 8, 16, 24, 32, and 40 mg/m2, and 4 schedules: 1, 2, 3, or 4 cycles, each with 5 days of drug and 25 days of rest. Cycle 1 started on Day +40. RESULTS: Reversible thrombocytopenia was the dose-limiting toxicity. The optimal combination was 32 mg/m2 given for 4 cycles. Median follow-up was 20.5 months. One-year event-free and overall survival were 58% and 77%, justifying further studies to estimate long-term clinical benefit. No dose significantly affected DNA global methylation. CONCLUSIONS: Azacitidine at 32 mg/m2 given for 5 days is safe and can be administered after allogeneic transplant for at least 4 cycles to heavily pretreated AML/MDS patients. The trial also suggested that this treatment may prolong event-free and overall survival, and that more cycles may be associated with greater benefit. Cancer 2010. © 2010 American Cancer Society.
Hyangmin Byun - One of the best experts on this subject based on the ideXlab platform.
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2 deoxy n4 2 4 nitrophenyl ethoxycarbonyl 5 azacytidine a novel inhibitor of dna methyltransferase that requires activation by human carboxylesterase 1
Cancer Letters, 2008Co-Authors: Hyangmin Byun, Si Ho Choi, Peter W Laird, Maqbool A Siddiqui, Victor E Marquez, Binh N Trinh, Allen S YangAbstract:2’-Deoxy-N4-[2-(4-nitrophenyl) ethoxycarbonyl]-5-azacytidine (NPEOC-DAC), decitabine with a modification of the N4 position of the Azacitidine ring can be used to inhibit DNA methyltransferase. This modification protects the Azacitidine ring and can be cleaved by carboxylesterase to release decitabine. NPEOC-DAC was 23-fold less potent at low doses (<10 µM) than decitabine at inhibiting DNA methylation, and was also associated with a 3-day delay in its effect. However, at doses ≥ 10 µM NPEOC-DAC was more effective at inhibiting DNA methylation. Theses differences between decitabine and NPEOC-DAC are dependent on the cleavage of the carboxylester bond, and could be potentially exploited pharmacologically.
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2 deoxy n4 2 4 nitrophenyl ethoxycarbonyl 5 azacytidine a novel inhibitor of dna methyltransferase that requires activation by human carboxylesterase 1
Cancer Letters, 2008Co-Authors: Hyangmin Byun, Si Ho Choi, Peter W Laird, B Trinh, Maqbool A Siddiqui, Victor E Marquez, Allen S YangAbstract:2'-Deoxy-N4-[2-(4-nitrophenyl)ethoxycarbonyl]-5-azacytidine (NPEOC-DAC), decitabine with a modification of the N4 position of the Azacitidine ring can be used to inhibit DNA methyltransferase. This modification protects the Azacitidine ring and can be cleaved by carboxylesterase to release decitabine. NPEOC-DAC was 23-fold less potent at low doses ( or = 10microM NPEOC-DAC was more effective at inhibiting DNA methylation. Theses differences between decitabine and NPEOC-DAC are dependent on the cleavage of the carboxylester bond, and could be potentially exploited pharmacologically.
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hydroxycarbamide in combination with Azacitidine or decitabine is antagonistic on dna methylation inhibition
British Journal of Haematology, 2007Co-Authors: Si Ho Choi, Hyangmin Byun, Jennifer M Kwan, Jean Pierre J Issa, Allen S YangAbstract:Azacitidine and decitabine are cytidine analogues that inhibit DNA methylation, and are used to treat myeloid haematological malignancies. Hydroxycarbamide (HC) (also known as hydroxyurea), a ribonucleotide reductase (RR) inhibitor, blocks the conversion of ribonucleotides to deoxyribonucleotides, and is also used to treat leukaemia and sickle-cell disease. Azacitidine is a ribonucleoside and decitabine is a deoxyribonucleoside; therefore, we hypothesized that inhibition of RR by HC would be antagonistic to Azacitidine and synergistic to decitabine. HL-60 and T24 cancer cell lines were treated with Azacitidine or decitabine in combination with HC and DNA methylation of LRE1, MAGEA1 and CDKN2A was quantitatively measured by bisulphite-polymerase chain reaction pyrosequencing. Surprisingly, we found that HC blocked the ability of both Azacitidine and decitabine to inhibit DNA methylation and this antagonistic effect was attributable to the arrest of the cell cycle induced by HC. However, this antagonism could be avoided with sequential treatment of HC followed by Azacitidine or decitabine. This data suggest that concurrent combination of HC blocks the ability of Azacitidine and decitabine to inhibit DNA methylation and therefore these drugs should be used sequentially.
Si Ho Choi - One of the best experts on this subject based on the ideXlab platform.
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2 deoxy n4 2 4 nitrophenyl ethoxycarbonyl 5 azacytidine a novel inhibitor of dna methyltransferase that requires activation by human carboxylesterase 1
Cancer Letters, 2008Co-Authors: Hyangmin Byun, Si Ho Choi, Peter W Laird, Maqbool A Siddiqui, Victor E Marquez, Binh N Trinh, Allen S YangAbstract:2’-Deoxy-N4-[2-(4-nitrophenyl) ethoxycarbonyl]-5-azacytidine (NPEOC-DAC), decitabine with a modification of the N4 position of the Azacitidine ring can be used to inhibit DNA methyltransferase. This modification protects the Azacitidine ring and can be cleaved by carboxylesterase to release decitabine. NPEOC-DAC was 23-fold less potent at low doses (<10 µM) than decitabine at inhibiting DNA methylation, and was also associated with a 3-day delay in its effect. However, at doses ≥ 10 µM NPEOC-DAC was more effective at inhibiting DNA methylation. Theses differences between decitabine and NPEOC-DAC are dependent on the cleavage of the carboxylester bond, and could be potentially exploited pharmacologically.
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2 deoxy n4 2 4 nitrophenyl ethoxycarbonyl 5 azacytidine a novel inhibitor of dna methyltransferase that requires activation by human carboxylesterase 1
Cancer Letters, 2008Co-Authors: Hyangmin Byun, Si Ho Choi, Peter W Laird, B Trinh, Maqbool A Siddiqui, Victor E Marquez, Allen S YangAbstract:2'-Deoxy-N4-[2-(4-nitrophenyl)ethoxycarbonyl]-5-azacytidine (NPEOC-DAC), decitabine with a modification of the N4 position of the Azacitidine ring can be used to inhibit DNA methyltransferase. This modification protects the Azacitidine ring and can be cleaved by carboxylesterase to release decitabine. NPEOC-DAC was 23-fold less potent at low doses ( or = 10microM NPEOC-DAC was more effective at inhibiting DNA methylation. Theses differences between decitabine and NPEOC-DAC are dependent on the cleavage of the carboxylester bond, and could be potentially exploited pharmacologically.
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hydroxycarbamide in combination with Azacitidine or decitabine is antagonistic on dna methylation inhibition
British Journal of Haematology, 2007Co-Authors: Si Ho Choi, Hyangmin Byun, Jennifer M Kwan, Jean Pierre J Issa, Allen S YangAbstract:Azacitidine and decitabine are cytidine analogues that inhibit DNA methylation, and are used to treat myeloid haematological malignancies. Hydroxycarbamide (HC) (also known as hydroxyurea), a ribonucleotide reductase (RR) inhibitor, blocks the conversion of ribonucleotides to deoxyribonucleotides, and is also used to treat leukaemia and sickle-cell disease. Azacitidine is a ribonucleoside and decitabine is a deoxyribonucleoside; therefore, we hypothesized that inhibition of RR by HC would be antagonistic to Azacitidine and synergistic to decitabine. HL-60 and T24 cancer cell lines were treated with Azacitidine or decitabine in combination with HC and DNA methylation of LRE1, MAGEA1 and CDKN2A was quantitatively measured by bisulphite-polymerase chain reaction pyrosequencing. Surprisingly, we found that HC blocked the ability of both Azacitidine and decitabine to inhibit DNA methylation and this antagonistic effect was attributable to the arrest of the cell cycle induced by HC. However, this antagonism could be avoided with sequential treatment of HC followed by Azacitidine or decitabine. This data suggest that concurrent combination of HC blocks the ability of Azacitidine and decitabine to inhibit DNA methylation and therefore these drugs should be used sequentially.
Alan F List - One of the best experts on this subject based on the ideXlab platform.
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randomized phase ii study of Azacitidine alone or in combination with lenalidomide or with vorinostat in higher risk myelodysplastic syndromes and chronic myelomonocytic leukemia north american intergroup study swog s1117
Journal of Clinical Oncology, 2017Co-Authors: Mikkael A Sekeres, Steven D Gore, Alan F List, Megan Othus, Olatoyosi Odenike, Richard Stone, Mark R Litzow, Rena Buckstein, Min Fang, Diane RoulstonAbstract:PurposeAzacitidine is standard, first-line therapy in higher-risk myelodysplastic syndromes (MDS). Whether Azacitidine-based combinations with lenalidomide or vorinostat produce superior overall response rates (ORRs) to Azacitidine is not known.Patients and MethodsNorth American Intergroup Study S1117 is a phase II/III trial that randomly assigned patients with higher-risk MDS and chronic myelomonocytic leukemia (CMML) 1:1:1 to Azacitidine (75 mg/m2/day on days 1 to 7 of a 28-day cycle); Azacitidine plus lenalidomide (10 mg/day on days 1 to 21); or Azacitidine plus vorinostat (300 mg twice daily on days 3 to 9). The primary phase II end point was improved ORR.ResultsOf 277 patients from 90 centers, 92 received Azacitidine, 93 received Azacitidine plus lenalidomide, and 92 received Azacitidine plus vorinostat. Median age was 70 years (range, 28 to 93 years), 85 patients (31%) were female, and 53 patients (19%) had CMML. Serious adverse events were similar across arms, although combination-arm patients were...
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predictive factors of response and survival among chronic myelomonocytic leukemia patients treated with Azacitidine
Leukemia Research, 2013Co-Authors: Lionel Ades, Raphael Itzykson, Alan F List, Mikkael A Sekeres, Alice Wolfromm, Melissa L Teichman, Ramon V Tiu, Jaroslaw P Maciejewski, Francois Dreyfus, Pierre FenauxAbstract:Treatment of CMML remains a clinical challenge, with no drug demonstrating clear clinical benefit. Even if Azacitidine is approved in the treatment of CMML, its role remains disputed. We report a cohort of 76 CMML patients (according to WHO classification) treated with Azacitidine in 3 programs (French AZA compassionate program, Cleveland Clinic Foundation and H. Lee Moffitt Cancer Center). 45% had CMML2, and 55% had splenomegaly and/or WBC counts >13 G/L, which are known to be poor prognostic factors in CMML. All patients received AZA for at least one cycle, and the median number of cycles administered was 6. Thirty-three patients (43%) achieved a response according to IWG 2006 criteria, including 13 complete remissions (17%). Median survival was 29 months. Increased bone marrow blast percentage and proliferative features of the disease, including splenomegaly and high WBC counts, were significantly associated with shorter survival. By multivariate analysis, only marrow blasts >10% and palpable splenomegaly had prognostic impact on survival. Although promising, the efficacy of Azacitidine in advanced CMML needs to be confirmed in a randomized prospective study.
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continued Azacitidine therapy beyond time of first response improves quality of response in patients with higher risk myelodysplastic syndromes
Cancer, 2011Co-Authors: Lewis R Silverman, Pierre Fenaux, Norbert Gattermann, Eva Hellstromlindberg, Ghulam J Mufti, Steven D Gore, Alan F List, Valeria Santini, Guillermo Sanz, John F SeymourAbstract:BACKGROUND: In the AZA-001 trial, Azacitidine (75 mg/m2/d subcutaneously for Days 1-7 of every 28-day cycle) demonstrated improved survival compared with conventional care regimens in patients with International Prognostic Scoring System-defined intermediate-2- or high-risk myelodysplastic syndrome and World Health Organization-defined acute myeloid leukemia with 20% to 30% bone marrow blasts. METHODS: This secondary analysis of the AZA-001 phase 3 study evaluated the time to first response and the potential benefit of continued Azacitidine treatment beyond first response in responders. RESULTS: Overall, 91 of 179 patients achieved a response to Azacitidine; responding patients received a median of 14 treatment cycles (range, 2-30). Median time to first response was 2 cycles (range, 1-16). Although 91% of first responses occurred by 6 cycles, continued Azacitidine improved response category in 48% of patients. Best response was achieved by 92% of responders by 12 cycles. Median time from first response to best response was 3.5 cycles (95% confidence interval [CI], 3.0-6.0) in 30 patients who ultimately achieved a complete response, and 3.0 cycles (95% CI, 1.0-3.0) in 21 patients who achieved a partial response. CONCLUSIONS: Continued Azacitidine therapy in responders was associated with a quantitative increase in response to a higher response category in 48% of patients, and therefore may enhance clinical benefit in patients with higher-risk MDS. Cancer 2011. © 2011 American Cancer Society.
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prolonged survival with improved tolerability in higher risk myelodysplastic syndromes Azacitidine compared with low dose ara c
British Journal of Haematology, 2010Co-Authors: Pierre Fenaux, Norbert Gattermann, John F Seymour, Eva Hellstromlindberg, Ghulam J Mufti, Ulrich Duehrsen, Steven D Gore, Fernando Ramos, O Beynerauzy, Alan F ListAbstract:In the phase III AZA-001 trial, low-dose cytarabine (LDara-C), the most widely used low-dose chemotherapy in patients with higher-risk myelodysplastic syndrome (MDS) who are ineligible for intensive treatment, was found to be associated with poorer survival compared with Azacitidine. This analysis further compared the efficacy and the toxicity of these two drug regimens. Before randomization, investigators preselected patients to receive a conventional care regimen, one of which was LDara-C. Of 94 patients preselected to LDara-C, 45 were randomized to Azacitidine and 49 to LDara-C. Azacitidine patients had significantly more and longer haematological responses and increased red blood cell transfusion independence. Azacitidine prolonged overall survival versus LDara-C in patients with poor cytogenetic risk, presence of -7/del(7q), and French-American-British subtypes refractory anaemia with excess blasts (RAEB) and RAEB in transformation. When analyzed per patient year of drug exposure, Azacitidine treatment was associated with fewer grade 3-4 cytopenias and shorter hospitalisation time than LDara-C in these higher-risk MDS patients.
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Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia
Journal of Clinical Oncology, 2010Co-Authors: Pierre Fenaux, Norbert Gattermann, Eva Hellstromlindberg, Ghulam J Mufti, Steven D Gore, Alan F List, Valeria Santini, Ulrich Germing, Guillermo Sanz, John F SeymourAbstract:Purpose In a phase III randomized trial, Azacitidine significantly prolonged overall survival (OS) compared with conventional care regimens (CCRs) in patients with intermediate-2– and high-risk myelodysplastic syndromes. Approximately one third of these patients were classified as having acute myeloid leukemia (AML) under current WHO criteria. This analysis compared the effects of Azacitidine versus CCR on OS in this subgroup. Patients and Methods Patients were randomly assigned to receive subcutaneous Azacitidine 75 mg/m 2 /d or CCR (best supportive care [BSC] only, low-dose cytarabine (LDAC), or intensive chemotherapy [IC]). Results Of the 113 elderly patients (median age, 70 years) randomly assigned to receive Azacitidine (n 55) or CCR (n 58; 47% BSC, 34% LDAC, 19% IC), 86% were considered unfit for IC. At a median follow-up of 20.1 months, median OS for Azacitidine-treated patients was 24.5 months compared with 16.0 months for CCR-treated patients (hazard ratio 0.47; 95% CI, 0.28 to 0.79; P .005), and 2-year OS rates were 50% and 16%, respectively (P .001). Two-year OS rates were higher with Azacitidine versus CCR in patients considered unfit for IC (P .0003). Azacitidine was associated with fewer total days in hospital (P .0001) than CCR. Conclusion In older adult patients with low marrow blast count (20% to 30%) WHO-defined AML, Azacitidine significantly prolongs OS and significantly improves several patient morbidity measures compared with CCR.