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1.
FASEB J ; 36(1): e22094, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34888943

RESUMO

Modifications in sphingolipid (SL) metabolism and mitochondrial bioenergetics are key factors implicated in cancer cell response to chemotherapy, including chemotherapy resistance. In the present work, we utilized acute myeloid leukemia (AML) cell lines, selected to be refractory to various chemotherapeutics, to explore the interplay between SL metabolism and mitochondrial biology supportive of multidrug resistance (MDR). In agreement with previous findings in cytarabine or daunorubicin resistant AML cells, relative to chemosensitive wildtype controls, HL-60 cells refractory to vincristine (HL60/VCR) presented with alterations in SL enzyme expression and lipidome composition. Such changes were typified by upregulated expression of various ceramide detoxifying enzymes, as well as corresponding shifts in ceramide, glucosylceramide, and sphingomyelin (SM) molecular species. With respect to mitochondria, despite consistent increases in both basal respiration and maximal respiratory capacity, direct interrogation of the oxidative phosphorylation (OXPHOS) system revealed intrinsic deficiencies in HL60/VCR, as well as across multiple MDR model systems. Based on the apparent requirement for augmented SL and mitochondrial flux to support the MDR phenotype, we explored a combinatorial therapeutic paradigm designed to target each pathway. Remarkably, despite minimal cytotoxicity in peripheral blood mononuclear cells (PBMC), co-targeting SL metabolism, and respiratory complex I (CI) induced synergistic cytotoxicity consistently across multiple MDR leukemia models. Together, these data underscore the intimate connection between cellular sphingolipids and mitochondrial metabolism and suggest that pharmacological intervention across both pathways may represent a novel treatment strategy against MDR.


Assuntos
Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Leucemia/metabolismo , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Esfingolipídeos/metabolismo , Citarabina/farmacologia , Daunorrubicina/farmacologia , Células HL-60 , Humanos , Leucemia/patologia , Mitocôndrias/patologia , Vincristina/farmacologia
2.
Anal Chem ; 93(44): 14773-14777, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34699191

RESUMO

Drug delivery systems using nanoparticles are currently in the panorama of nanomedicine studies. In oncology, chemotherapeutic regimens using anthracycline antibiotics rely on the dosage of treatments to minimize the severity of side effects on the patient. Therefore, even in targeted delivery systems it is of great importance to quantify the level of drug administrated for dosage and quality control of the treatment. Herein, as a feasible pathway to shed light on improving nano drug quantification procedures, we proposed a simple analytical protocol to quantify the anthracyclines loaded on our nonchiral carbon nitride dots (CNDs) with circular dichroism spectrometry (CD). The calibration curves from the linear relation between ellipticity and concentration of the anthracycline drugs followed by measurements on the CNDs conjugates were used in achieving the quantification technique which showed different drug loading for each anthracycline used such as daunorubicin, doxorubicin, and epirubicin.


Assuntos
Preparações Farmacêuticas , Antraciclinas , Antibacterianos , Antibióticos Antineoplásicos , Carbono , Dicroísmo Circular , Daunorrubicina , Doxorrubicina , Humanos
3.
J Ayub Med Coll Abbottabad ; 33(3): 475-479, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34487660

RESUMO

BACKGROUND: Diagnostic karyotyping analysis is routinely used in acute myeloid leukaemia (AML) clinics. Categorization of patients into risk stratified groups (favourable, intermediate and unfavourable) according to cytogenetic findings can serve as a valuable independent prognostic factor. The aim of this study was to assess the one-year disease free survival rate in AML patients after induction remission presenting at tertiary care hospital of Karachi. METHODS: It was a longitudinal study conducted at the department of Medical oncology of Jinnah Postgraduate Medical Center, Karachi from Jun 2017-Jan 2019. Ninety-three diagnosed cases of AML of age 15-55 years of either gender were included in the study. All patients received the first cycle of "3+7" regime for induction chemotherapy. This includes Daunorubicin 45 mg/m2 on days 1 to 3 and Cytarabine in a dose of 100 mg/m2 from day 1-7. Marrow response was assessed on the 21th day of induction therapy. If the bone marrow includes lesser than five percent blast cells then it was labelled as complete remission (CR). The patients who achieved CR and normal haematopoiesis were eligible to receive 4 cycles of consolidation therapy with cytarabine 3 mg/m2 every 12 hour on days 1, 3 and 5. Consolidation cycles were monthly administered. All the patients who achieved CR were follow up for the duration of one year for disease free survival. On follow up monthly visits, outcomes were assessed using CBC report and physical examination. RESULTS: After 1 year, out of 72 AML patients, 19 patients remained in complete remission, 5 patients lost to follow up, 3 relapses, 19 showed persistent disease & 28 died during consolidation. According to cytogenetic status, CR was achieved in 6 patients (50%) with favourable cytogenetic, 14 patients (28%) with intermediate cytogenetic and 2 patients (20%) with unfavourable cytogenetic status. The highest median survival time was observed in patients with favourable cytogenetic status as 5.23 months. However, there was no significant difference was observed in survival time with respect to cytogenetic status. CONCLUSIONS: The "3+7" regime of Daunorubicin & Cytarabine is effective in inducing induction remission and increases 1 year survival, however chemotherapy related morality rate was high in unfavourable cytogenetic group.


Assuntos
Leucemia Mieloide Aguda , Doença Aguda , Adolescente , Adulto , Citarabina , Daunorrubicina , Intervalo Livre de Doença , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Estudos Longitudinais , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Adulto Jovem
5.
Biochem Pharmacol ; 192: 114710, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34339712

RESUMO

Bcr-Abl tyrosine kinase inhibitors significantly improved Philadelphia chromosome-positive leukaemia therapy. Apart from Bcr-Abl kinase, imatinib, dasatinib, nilotinib, bosutinib and ponatinib are known to have additional off-target effects that might contribute to their antitumoural activities. In our study, we identified aldo-keto reductase 1B10 (AKR1B10) as a novel target for dasatinib. The enzyme AKR1B10 is upregulated in several cancers and influences the metabolism of chemotherapy drugs, including anthracyclines. AKR1B10 reduces anthracyclines to alcohol metabolites that show less antineoplastic properties and tend to accumulate in cardiac tissue. In our experiments, clinically achievable concentrations of dasatinib selectively inhibited AKR1B10 both in experiments with recombinant enzyme (Ki = 0.6 µM) and in a cellular model (IC50 = 0.5 µM). Subsequently, the ability of dasatinib to attenuate AKR1B10-mediated daunorubicin (Daun) resistance was determined in AKR1B10-overexpressing cells. We have demonstrated that dasatinib can synergize with Daun in human cancer cells and enhance its therapeutic effectiveness. Taken together, our results provide new information on how dasatinib may act beyond targeting Bcr-Abl kinase, which may help to design new chemotherapy regimens, including those with anthracyclines.


Assuntos
Aldo-Ceto Redutases/antagonistas & inibidores , Dasatinibe/administração & dosagem , Daunorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Células A549 , Aldo-Ceto Redutases/química , Aldo-Ceto Redutases/metabolismo , Antineoplásicos/administração & dosagem , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Proteínas de Fusão bcr-abl/química , Proteínas de Fusão bcr-abl/metabolismo , Células HCT116 , Humanos , Simulação de Acoplamento Molecular , Estrutura Secundária de Proteína
6.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(4): 1071-1079, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34362484

RESUMO

OBJECTIVE: To compare the efficacy and safety of different doses of daunorubicin combined with a standard dose of cytarabine as induction chemotherapy in newly diagnosed primary acute myeloid leukemia (AML) patients. METHODS: The clinical data and outcome were retrospectively analyzed in 86 newly diagnosed primary AML patients who were under 65 years old and treated with daunorubicin combined with cytarabine (DA regimen) at West China Hospital of Sichuan University from January 2017 to June 2019. Patients were divided into 2 groups based on the dose of daunorubicin they received, 35 cases in the escalated-dose group ï¼»75 mg/(m2·d)ï¼½ and 51 cases in the standard-dose group ï¼»60 mg/(m2·d)ï¼½. And then the effects of different doses of daunorubicin on complete remission (CR) rate, minimal residual disease (MRD)-negative CR rate, relapse-free survival (RFS), overall survival (OS), and adverse events were analyzed. RESULTS: Median follow-up time of all the patients was 15 months. The CR rate and MRD- CR rate of the escalated-dose group was 88.5% and 71.4%, respectively, which were higher than 64.7% and 41.2% of the standard-dose group (P=0.029, P=0.008). The estimated 2-year RFS of the escalated-dose group was 68.4%, which was higher than 38.5% of the standard-dose group (P=0.015), but estimated 2-year OS showed no statistically significant difference (77.1% vs 66.7%, P=0.059), as well as grade 3-4 adverse events. The escalated dose of daunorubicin had prolonged RFS (13 months vs not reached, P=0.022) and OS (23 months vs not reached, P=0.029) in the FLT3-ITD- AML patients. CONCLUSION: The escalated dose of daunorubicin can induce higher complete remission rate, deeper remission and longer duration of remission without increasing adverse events in newly diagnosed primary AML patients.


Assuntos
Daunorrubicina , Leucemia Mieloide Aguda , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Citarabina/uso terapêutico , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/tratamento farmacológico , Indução de Remissão , Estudos Retrospectivos
7.
J Control Release ; 338: 244-252, 2021 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-34416320

RESUMO

CPX-351 is a liposome encapsulating cytarabine and daunorubicin for treating Acute Myeloid Leukemia (AML) patients. To what extent differences in cytidine deaminase (CDA) activity, the enzyme that catabolizes free cytarabine in the liver, can affect the pharmacokinetics of liposomal cytarabine as well, is unknown. We have studied the pharmacokinetics (PK) of released, liposomal and total cytarabine using a population-modeling approach in 9 adult AML patients treated with liposomal CPX-351. Exposure levels and PK parameters were compared with respect to the patient's CDA status (i.e., Poor Metabolizer (PM) vs. Extensive Metabolizer (EM)). Overall response rate was 75%, and 56% of patients had non-hematological severe toxicities, including one lethal toxicity. All patients had febrile neutropenia. A large (>60%) inter-individual variability was observed on pharmacokinetics parameters and subsequent drug levels. A trend towards severe toxicities was observed in patients with higher exposure of cytarabine. Results showed that liposomal CPX-351 led to sustained exposure with reduced clearance (Cl = 0.16 L/h) and prolonged half-life (T1/2 = 28 h). Liposomal nanoparticles were observed transiently in bone marrow with cytarabine levels 2.3-time higher than in plasma. Seven out of 9 patients were PM with a strong impact on the PK parameters, i.e., PM patients showing higher cytarabine levels as compared with EM patients (AUC: 5536 vs. 1784 ng/mL.h), sustained plasma exposure (T1/2: 33.9 vs. 13.7 h), and reduced clearance (Cl: 0.12 vs. 0.29 L/h). This proof-of-concept study suggests that CDA status has a major impact on cytarabine PK and possibly safety in AML patients even when administered as a liposome.


Assuntos
Leucemia Mieloide Aguda , Farmacogenética , Adulto , Citarabina , Daunorrubicina , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética
8.
Biochem Biophys Res Commun ; 572: 138-144, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34364293

RESUMO

Heart diseases are known as the most primary causes of mortality worldwide. Although many therapeutic approaches and medications are proposed for these diseases, the identification of novel therapeutics in fatal heart conditions is promptly demanded. Besides, the interplay between gene expression data and molecular docking provides several novel insights to discover more effective and specific drugs for the treatment of the diseases. This study aimed to discover potent therapeutic drugs in the heart diseases based on the expression profile of heart-specific genes exclusively. Initially, the heart-specific and highly expressed genes were identified by comparing the gene expression profile of different body tissues. Subsequently, the druggable-genes were identified using in silico techniques. The interaction between these druggable genes with more than 1600 FDA approved drugs was then investigated using the molecular docking simulation. By comprehensively analyzing RNA-sequencing data obtained from 949 normal tissue samples, 48 heart-specific genes were identified in both the heart development and function. Notably, of these, 24 heart-specific genes were capable to be considered as druggable genes, among which only MYBPC3, MYLK3, and SCN5A genes entered the molecular docking process due to their functions. Afterward, the pharmacokinetics properties of top 10 ligands with the highest binding affinity for these proteins were studied. Accordingly, methylergonovine, fosaprepitant, pralatrexate, daunorubicin, glecaprevir, digoxin, and venetoclax drugs were competent, in order to interact with the target proteins perfectly. It was shown that these medications can be used as specific drugs for the treatment of heart diseases after fulfilling further experiments in this regard.


Assuntos
Cardiopatias/tratamento farmacológico , Simulação de Acoplamento Molecular , Ácidos Aminoisobutíricos/uso terapêutico , Aminopterina/análogos & derivados , Aminopterina/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Ciclopropanos/uso terapêutico , Daunorrubicina/uso terapêutico , Digoxina/uso terapêutico , Reposicionamento de Medicamentos , Expressão Gênica , Cardiopatias/genética , Humanos , Lactamas Macrocíclicas/uso terapêutico , Leucina/análogos & derivados , Leucina/uso terapêutico , Ligantes , Metilergonovina/uso terapêutico , Morfolinas/uso terapêutico , Prolina/análogos & derivados , Prolina/uso terapêutico , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico
9.
Turk J Pediatr ; 63(4): 639-647, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34449146

RESUMO

BACKGROUND: Chemotherapy with high dose methotrexate is the mainstay of treatment for Burkitt lymphoma (BL), especially to manage central nervous system (CNS) disease. However, methotrexate administration requires close drug level monitoring for appropriate folinic acid rescue, which might not be readily available in all centers. In this study, we assessed the long-term treatment outcomes of a modified Non-Hodgkin lymphoma (NHL)-Berlin-Frankfurt-Munster (BFM) 90 regimen in pediatric high-risk BL without CNS involvement. METHODS: Between 1999 and 2011, 42 patients (median age: 7 years) with advanced-stage BL were treated with modified NHL-BFM 90 regimen (methotrexate at a dose of 1 g/m2). Demographic data, stage, lactate dehydrogenase (LDH) and treatment results were retrospectively evaluated. The patients were assessed for toxicity, survival and CNS recurrence. RESULTS: Thirty-six patients had Stage III and six had Stage IV disease, respectively. The median LDH level was 1,432 IU/L. Four patients died of infectious and metabolic complications. One patient had local recurrence at the 48 < sup > th < /sup > month of the follow-up and he is in the second remission for 72 months. In Kaplan-Meier analysis, the overall survival and event-free survival rates at 10 years were found as 90 % and 88 %, respectively. None of our patients died of treatment failure. CONCLUSIONS: The administration of the reduced dose of methotrexate seems to not compromise treatment success nor increase the risk of CNS recurrence in high-risk BL without CNS involvement. The limitation of the study is that it is not randomized. Our treatment scheme might be considered for centers without methotrexate measurement facility.


Assuntos
Linfoma de Burkitt , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase , Linfoma de Burkitt/tratamento farmacológico , Criança , Daunorrubicina , Humanos , Masculino , Recidiva Local de Neoplasia , Prednisona , Estudos Retrospectivos , Resultado do Tratamento , Vincristina
10.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298882

RESUMO

Platelets can modulate cancer through budding of platelet microparticles (PMPs) that can transfer a plethora of bioactive molecules to cancer cells upon internalization. In acute myelogenous leukemia (AML) this can induce chemoresistance, partially through a decrease in cell activity. Here we investigated if the internalization of PMPs protected the monocytic AML cell line, THP-1, from apoptosis by decreasing the initial cellular damage inflicted by treatment with daunorubicin, or via direct modulation of the apoptotic response. We examined whether PMPs could protect against apoptosis after treatment with a selection of inducers, primarily associated with either the intrinsic or the extrinsic apoptotic pathway, and protection was restricted to the agents targeting intrinsic apoptosis. Furthermore, levels of daunorubicin-induced DNA damage, assessed by measuring gH2AX, were reduced in both 2N and 4N cells after PMP co-incubation. Measuring different BCL2-family proteins before and after treatment with daunorubicin revealed that PMPs downregulated the pro-apoptotic PUMA protein. Thus, our findings indicated that PMPs may protect AML cells against apoptosis by reducing DNA damage both dependent and independent of cell cycle phase, and via direct modulation of the intrinsic apoptotic pathway by downregulating PUMA. These findings further support the clinical relevance of platelets and PMPs in AML.


Assuntos
Apoptose/fisiologia , Micropartículas Derivadas de Células/fisiologia , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/fisiologia , Daunorrubicina/farmacologia , Células THP-1/fisiologia , Apoptose/efeitos dos fármacos , Plaquetas , Micropartículas Derivadas de Células/efeitos dos fármacos , Micropartículas Derivadas de Células/metabolismo , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Células THP-1/efeitos dos fármacos , Células THP-1/metabolismo
11.
J Hematol Oncol ; 14(1): 110, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34256819

RESUMO

BACKGROUND: CPX-351 (United States: Vyxeos®; Europe: Vyxeos® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved by the US FDA and the EMA for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In a pivotal phase 3 study that evaluated 309 patients aged 60 to 75 years with newly diagnosed high-risk/secondary acute myeloid leukemia, CPX-351 significantly improved median overall survival versus conventional 7 + 3 chemotherapy (cytarabine continuous infusion for 7 days plus daunorubicin for 3 days), with a comparable safety profile. A Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of the phase 3 study was performed to compare survival quality between patients receiving CPX-351 versus conventional 7 + 3 after 5 years of follow-up. METHODS: Patients were randomized 1:1 between December 20, 2012 and November 11, 2014 to receive induction with CPX-351 or 7 + 3. Survival time for each patient was partitioned into 3 health states: TOX (time with any grade 3 or 4 toxicity or prior to remission), TWiST (time in remission without relapse or grade 3 or 4 toxicity), and REL (time after relapse). Within each treatment arm, Q-TWiST was calculated by adding the mean time spent in each health state weighted by its respective quality-of-life, represented by health utility. The relative Q-TWiST gain, calculated as the difference in Q-TWiST between treatment arms divided by the mean survival of the 7 + 3 control arm, was determined in order to evaluate results in the context of other Q-TWiST analyses. RESULTS: The relative Q-TWiST gain with CPX-351 versus 7 + 3 was 53.6% in the base case scenario and 39.8% among responding patients. Across various sensitivity analyses, the relative Q-TWiST gains for CPX-351 ranged from 48.0 to 57.6%, remaining well above the standard clinically important difference threshold of 15% for oncology. CONCLUSIONS: This post hoc analysis demonstrates that CPX-351 improved quality-adjusted survival, further supporting the clinical benefit in patients with newly diagnosed high-risk/secondary acute myeloid leukemia. Trial registration This trial was registered on September 28, 2012 at www.clinicaltrials.gov as NCT01696084 ( https://clinicaltrials.gov/ct2/show/NCT01696084 ) and is complete.


Assuntos
Antineoplásicos/uso terapêutico , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/epidemiologia , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/epidemiologia , Qualidade de Vida , Análise de Sobrevida
12.
Medicine (Baltimore) ; 100(23): e26323, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115047

RESUMO

RATIONALE: B-lymphoblastic lymphoma (B-LBL) with BCR/ABL mutation (Ph+ B-LBL) is a rare type of cancer in both childhood and adults. Its clinical manifestations are similar to those of other types lymphoma. However, the targeted therapy can substantially improve the outcome of Ph+ B-LBL. PATIENT CONCERNS: A 19-year-old male with blood type O, Rh+ was admitted into our hospital on August 14, 2018, due to a recurrent fever and hypocytosis for 6 months. DIAGNOSES: Routine blood exam showed pancytopenia. Bone marrow sample flow cytometry (FCM) exam showed abnormal cells were 2.27% of the nucleated cells, and was classified as the abnormal early B-lineage lymphoblastic cells. FISH testing showed the BCR/ABL positive cells were 13.6%. Karyotype analysis showed the 46, XY, t(9;22)(q34;q11). Molecular analysis of BCR/ABL mutation on ABL kinase showed that BCR/ABL T315I mutation. Patient was diagnosed with B-LBL with BCR/ABL mutation (Ph+ B-LBL). INTERVENTIONS: The patient was given chemotherapy with VDPI regimen (Vinorelbine, daunorubicin, prednisone, imatinib). OUTCOMES: The patient achieved complete remission after 2 courses' treatment, followed by one course of clarithromycin regimen and another two courses of VDPI regimen. Patient remains in complete remission as of March 10, 2021. LESSONS: In B-LBL, a BCR/ABL mutation can happen in some of these patients. It is important to guide the pathologist to perform appropriate gene mutation detection, in addition to routine Immunohistochemistry test, to ensure an accurate diagnosis and use the targeted agent for treatment. According to the literature and our results, it seems that intensive chemotherapy plus TKI regimen is effective in inducing complete remission, and allo-SCT should be used as a long-term strategy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Proteínas de Fusão bcr-abl/genética , Mesilato de Imatinib/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras , Exame de Medula Óssea/métodos , Daunorrubicina/administração & dosagem , Testes Genéticos/métodos , Humanos , Masculino , Mutação , Variantes Farmacogenômicos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia , Prednisona/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Indução de Remissão/métodos , Resultado do Tratamento , Vincristina/administração & dosagem , Adulto Jovem
14.
Lancet Haematol ; 8(7): e481-e491, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34171279

RESUMO

BACKGROUND: Daunorubicin and cytarabine are used as standard induction chemotherapy for patients with acute myeloid leukaemia. CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. Primary analysis of the phase 3 trial in adults aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia provided support for approval of CPX-351 by the US Food and Drug Administration and European Medicines Agency. We describe the prospectively planned final 5-year follow-up results. METHODS: This randomised, open-label, multicentre, phase 3 trial was done across 39 academic and regional cancer centres in the USA and Canada. Eligible patients were aged 60-75 years and had a pathological diagnosis of acute myeloid leukaemia according to WHO 2008 criteria, no previous induction therapy for acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned 1:1 (stratified by age and acute myeloid leukaemia subtype) to receive up to two induction cycles of CPX-351 (100 units/m2 administered as a 90-min intravenous infusion on days 1, 3, and 5; on days 1 and 3 for the second induction) or standard chemotherapy (cytarabine 100 mg/m2 per day continuous intravenous infusion for 7 days plus intravenous daunorubicin 60 mg/m2 on days 1, 2, and 3 [7+3]; cytarabine for 5 days and daunorubicin on days 1 and 2 for the second induction [5+2]). Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery could receive up to tw cycles of consolidation therapy with CPX-351 (65 units/m2 90-min infusion on days 1 and 3) or chemotherapy (5+2, same dosage as in the second induction cycle). The primary outcome was overall survival analysed in all randomly assigned patients. No additional adverse events were collected with long-term follow-up, except data for deaths. This trial is registered with ClinicalTrials.gov, NCT01696084, and is complete. FINDINGS: Between Dec 20, 2012, and Nov 11, 2014, 309 patients with newly diagnosed high-risk or secondary acute myeloid leukaemia were enrolled and randomly assigned to receive CPX-351 (153 patients) or 7+3 (156 patients). At a median follow-up of 60·91 months (IQR 60·06-62·98) in the CPX-351 group and 59·93 months (59·73-60·50) in the 7+3 group, median overall survival was 9·33 months (95% CI 6·37-11·86) with CPX-351 and 5·95 months (4·99-7·75) with 7+3 (HR 0·70, 95% CI 0·55-0·91). 5-year overall survival was 18% (95% CI 12-25%) in the CPX-351 group and 8% (4-13%) in the 7+3 group. The most common cause of death in both groups was progressive leukaemia (70 [56%] of 124 deaths in the CPX-351 group and 74 [53%] of 140 deaths in the 7+3 group). Six (5%) of 124 deaths in the CPX-351 group and seven (5%) of 140 deaths in the 7+3 group were considered related to study treatment. INTERPRETATION: After 5 years of follow-up, the improved overall survival with CPX-351 versus 7+3 was maintained, which supports the previous evidence that CPX-351 can contribute to long-term remission and improved overall survival in patients aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia. FUNDING: Jazz Pharmaceuticals.


Assuntos
Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Infusões Intravenosas , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária , Modelos de Riscos Proporcionais , Resultado do Tratamento
15.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068078

RESUMO

Anthracyclines remain a cornerstone of induction chemotherapy for acute myeloid leukemia (AML). Refractory or relapsed disease due to chemotherapy resistance is a major obstacle in AML management. MicroRNAs (miRNAs) have been observed to be involved in chemoresistance. We previously observed that miR-15a-5p was overexpressed in a subgroup of chemoresistant cytogenetically normal AML patients compared with chemosensitive patients treated with daunorubicin and cytarabine. MiR-15a-5p overexpression in AML cells reduced apoptosis induced by both drugs in vitro. This study aimed to elucidate the mechanisms by which miR-15a-5p contributes to daunorubicin resistance. We showed that daunorubicin induced autophagy in myeloid cell lines. The inhibition of autophagy reduced cell sensitivity to daunorubicin. The overexpression of miR-15a-5p decreased daunorubicin-induced autophagy. Conversely, the downregulation of miR-15a-5p increased daunorubicin-induced autophagy. We found that miR-15a-5p targeted four genes involved in autophagy, namely ATG9a, ATG14, GABARAPL1 and SMPD1. Daunorubicin increased the expression of these four genes, and miR-15a-5p counteracted this regulation. Inhibition experiments with the four target genes showed the functional effect of miR-15a-5p on autophagy. In summary, our results indicated that miR-15a-5p induces chemoresistance in AML cells through the abrogation of daunorubicin-induced autophagy, suggesting that miR-15a-5p could be a promising therapeutic target for chemoresistant AML patients.


Assuntos
Biomarcadores Tumorais/metabolismo , Daunorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Leucemia Mieloide Aguda/tratamento farmacológico , MicroRNAs/genética , Adulto , Antibióticos Antineoplásicos/farmacologia , Apoptose , Autofagia , Biomarcadores Tumorais/genética , Proliferação de Células , Perfilação da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Células Tumorais Cultivadas
16.
Asian Pac J Cancer Prev ; 22(5): 1407-1412, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34048168

RESUMO

BACKGROUND: Daunorubicine, a type of anthracycline, is a drug commonly used in cancer chemotherapy that increases survival rate but consequently compromises with cardiovascular outcomes in some patients. Thus, preventing the early progression of cardiotoxicity is important to improve the treatment outcome in childhood acute lymhoblastic leukemia (ALL). OBJECTIVE: The present study aimed to identify the risk factors in anthracycline-induced early cardiotoxicity in childhood ALL. METHODS: This retrospective study was conducted by observing ALL-diagnosed children from 2014 to 2019 in Dr. Soetomo General Hospital. There were 49 patients who met the inclusion criteria and were treated with chemotherapy using Indonesian Childhood ALL Protocol 2013. Echocardiography was performed by pediatric cardiologists to compare before and at any given time after anthracycline therapy. Early cardiotoxicity was defined as a decline of left ventricle ejection fraction (LVEF) greater than 10% with a final LVEF < 53% during the first year of anthracycline administration.  Risk factors such as sex, age, risk stratification group, and cumulative dose were identified by using multiple logistic regression. Diagnostic performance of cumulative anthracycline dose was evaluated by receiver operating characteristic (ROC) curve. RESULTS: Early anthracycline-induced cardiotoxicity was observed in 5 out of 49 patients. The median cumulative dose of anthracycline was 143.69±72.68 mg/m2. Thirty-three patients experienced a decreasing LVEF. The factors associated with early cardiomyopathy were age of ≥ 4 years (PR= 1.128; 95% CI: 1.015-1.254; p= 0.001), high risk group (PR= 1.135; 95% CI: 1.016-1.269; p= 0.001), and cumulative dose of ≥120 mg / m2 (CI= 1.161; 95% CI:1.019-1.332). CONCLUSION: Age of ≥ 4 years, risk group, and cumulative dose of ≥120 mg/m2 are significant risk factors for early cardiomyopathy in childhood ALL.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxicidade/patologia , Daunorrubicina/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Cardiotoxicidade/epidemiologia , Cardiotoxicidade/etiologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Indonésia/epidemiologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de Risco
17.
Biol Chem ; 402(4): 461-468, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33938176

RESUMO

The chemoresistance is one of the major challenges for acute myeloid leukemia (AML) treatment. We found that the expression of histone deacetylase 8 (HDAC8) was increased in daunorubicin (DNR) resistant AML cells, while targeted inhibition of HDAC8 by its specific siRNA or inhibitor can restore sensitivity of DNR treatment . Further, targeted inhibition of HDAC8 can suppress expression of interleukin 6 (IL-6) and IL-8. While recombinant IL-6 (rIL-6) and rIL-8 can reverse si-HDAC8-resored DNR sensitivity of AML cells. Mechanistical study revealed that HDAC8 increased the expression of p65, one of key components of NF-κB complex, to promote the expression of IL-6 and IL-8. It might be due to that HDAC8 can directly bind with the promoter of p65 to increase its transcription and expression. Collectively, our data suggested that HDAC8 promotes DNR resistance of human AML cells via regulation of IL-6 and IL-8.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Daunorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Histona Desacetilases/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Repressoras/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Histona Desacetilases/genética , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/antagonistas & inibidores , Interleucina-8/genética , Interleucina-8/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , RNA Interferente Pequeno/farmacologia , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Células Tumorais Cultivadas
19.
Sci Rep ; 11(1): 10017, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976256

RESUMO

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation and epigenetic deregulation. We assessed the prognostic significance of IDH1/2 mutations (IDH1/2+) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. IDH2 mutation was an independent favorable prognostic factor for 4-year overall survival (OS) in total NK-AML population (p = 0.03, censoring at allotransplant). We next evaluated the effect of addition of cladribine to induction regimen on the patients' outcome according to IDH1/2 mutation status. In DAC group, 4-year OS was increased in IDH2+ patients, compared to IDH-wild type group (54% vs 33%; p = 0.0087, censoring at allotransplant), while no difference was observed for DA-treated subjects. In multivariate analysis, DAC independently improved the survival of IDH2+ patients (HR = 0.6 [0.37-0.93]; p = 0.024; censored at transplant), indicating that this group specifically benefits from cladribine-containing therapy. In AML cells with R140Q or R172K IDH2 mutations, cladribine restrained mutations-related DNA hypermethylation. Altogether, DAC regimen produces better outcomes in IDH2+ NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/genética , Adolescente , Adulto , Idoso , Cladribina/uso terapêutico , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Polônia/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Adulto Jovem
20.
Biomed Pharmacother ; 140: 111744, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34049223

RESUMO

Endometrial cancer (EC) is the most common neoplasm of the female reproductive tract in the developed world. Patients usually are diagnosed in early stage having a good prognosis. However, up to 20-25% of patients are diagnosed in advanced stages and have a higher risk of recurrence, making the prognosis worse. Previously studies identified ANXA2 as a predictor of recurrent disease in EC even in low risk patients. Furthermore, Circulating Tumor Cells (CTC) released from the primary tumor into the bloodstream, are plasticity entities responsible of the process of metastasis, becoming into an attractive clinical target. In this work we validated ANXA2 expression in CTC from high-risk EC patients. After that, we modelled in vitro and in vivo the tumor cell attachment of ANXA2-expressing CTC to the endothelium and the homing for the generation of micrometastasis. ANXA2 overexpression does not provide an advantage in the adhesion process of CTC, but it could be playing an important role in more advanced steps, conferring a greater homing capacity. We also performed a high-throughput screening (HTS) for compounds specifically targeting ANXA2, and selected Daunorubicin as candidate hit. Finally, we validated Daunorubicin in a 3D transendothelial migration system and also in a in vivo model of advanced EC, demonstrating the ability of Daunorubicin to inhibit the proliferation of ANXA2-overexpressing tumor cells.


Assuntos
Anexina A2/metabolismo , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Animais , Anexina A2/genética , Adesão Celular , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Daunorrubicina/farmacologia , Daunorrubicina/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Endotélio/fisiologia , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Biópsia Líquida , Camundongos , Modelos Biológicos , Células Neoplásicas Circulantes
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