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1.
Asian Pac J Cancer Prev ; 24(1): 185-194, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36708567

RESUMO

BACKGROUND: Quantitative profiling of specific cell surface markers is a new approach in characterization of tumor heterogeneity and single cell biology. The current tools have dearth in detection and quantification of receptor proteins on single cells. METHODS: we focused on our newly developed protocol to determine the distribution pattern and density of cell surface markers on single acute myeloid leukemia cells. Cell surface proteins were labeled with quantum dots (Qdots) followed by super resolution Structured Illumination Microscopy (SIM) imaging to imprisonment the optical signals emitted by Qdots which were further analyzed by software imaris to do three dimensional (3D) structure reconstruction and digital simulation. Furthermore, MTT assays and flow cytometry was performed to establish association between expression of cell surface markers and drug response. RESULTS: In the present study, we found that the Molm13 and cytarabine-enriched Molm13 cells exhibit different densities of CD123, an alpha-subunit of interleukin-3 receptor, i.e. 0.92 and 1.73 per µm2 of cell surface respectively. Sub-populations of Molm13 cells expressing higher densities of CD123 on cells membranes showed resistance against cytarabine. Further study revealed that romidepsin sensitized and augmented the cytotoxicity of cytarabine in Molm13 and cytarabine-enriched Molm13 cells. Romidepsin increased the percentage of cell death-induced by cytarabine from 21.6 % to 28.6 % and 37.1 % to 57.2 % in Molm13 and cytarabine-enriched Molm13 cells respectively. CONCLUSION: Altogether, the study suggests that Molm13 cells have sub-populations with differential expression of CD123+ phenotype. Romidepsin sensitizes and augments the effect of cytarabine in Molm13 and cytarabine-enriched Molm13 cells.


Assuntos
Leucemia Mieloide Aguda , Receptores de Interleucina-3 , Humanos , Subunidade alfa de Receptor de Interleucina-3 , Leucemia Mieloide Aguda/patologia , Citarabina/farmacologia , Citometria de Fluxo , Linhagem Celular Tumoral
2.
Phytomedicine ; 109: 154605, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36610133

RESUMO

BACKGROUND: Intestinal mucositis (IM) is one of the common side effects of chemotherapy with Cytarabine (Ara-C) and contributes to the major dose-limiting factor of chemotherapy, while the effective drug for IM is little. Astragalus, one of the main active components extrated from the roots of Astragalus membranaceus (AS-IV), is a common Chinese herbal medicine used in gastrointestinal diseases. However, the effect and mechanism of AS-IV on IM is unclear. Accumulating evidence suggests that M1 macrophages play a pivotal role in IM progression. PURPOSE: The purpose of the study was to explore the protection of AS-IV and its potential molecular mechanism on intestinal mucositis injury induced by Ara-C. METHOD: The protective effect of AS-IV was investigated in LPS-induced macrophages and Ara-C-induced intestinal mucositis mouse model. H&E, immunofluorescence and western blotting were used to evaluate the damage in different doses of Ara-C. Silencing AKT targeted by siRNA was performed to explore the potential mechanisms regulating macrophage polarization effect of Ara-C, which was investigated by CCK-8, immunofluorescence and western blotting. Flow cytometry, immunofluorescence and Western blotting were used to detect macrophage surface marker proteins and inflammatory genes to explore the potential molecular mechanism of AS-IV regulating macrophage polarization. RESULTS: The Cytarabine intervention at dose of 100mg/kg significantly induced IM in mice, with the ileum the most obvious site of injury, accompanied by decreased intestinal barrier, intestinal macrophage polarization to M1 and inflammation response. The administration of AS-IV improved weight loss, food intake, ileal morphological damage, intestinal barrier destruction and inflammatory factor release in mice induced by Ara-c, and also suppressed macrophage polarization to M1, regulating in phenotypic changes in macrophages. In vitro, the expression of M1 macrophage surface marker protein was markedly decreased in LPS-induced macrophages after silencing AKT. Similarly, the western blotting of intestinal tissues and molecular docking indicated that the key mechanisms of AS-IV were remodel AKT signaling, and finally regulating M1 macrophages and decrease inflammation response. CONCLUSION: Our study highlights that AS-IV exerts protective effect in Ara-C-induced IM through inhibit polarization to M1 macrophages based on AKT, and AS-IV may serve as a novel AKT inhibitor to counteract the intestinal adverse effects of chemotherapeutic agents.


Assuntos
Citarabina , Mucosite , Proteínas Proto-Oncogênicas c-akt , Animais , Camundongos , Citarabina/efeitos adversos , Inflamação/tratamento farmacológico , Lipopolissacarídeos , Macrófagos , Proteínas de Membrana/metabolismo , Simulação de Acoplamento Molecular , Mucosite/induzido quimicamente , Mucosite/tratamento farmacológico , Mucosite/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
3.
ACS Appl Mater Interfaces ; 15(4): 5732-5743, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36688816

RESUMO

Carbon-based nanostructures are attracting a lot of attention because of their very low toxicity, excellent visible light-triggered optical and photothermal properties, and intriguing applications. Currently, the development of multifunctional carbon-based nanostructures for a synergistic chemo-photothermal approach is a challenging topic for the advancement of cancer treatment. Here, we report an unprecedented example of photoresponsive carbon-based polymer dots (CPDs-PNM) obtained by a one-pot thermal process from poly(N-isopropylacrylamide) (PNIPAM) without using organic solvent and additional reagents. The CPDs-PNM nanostructures were characterized by spectroscopic techniques, transmission electron microscopy, and atomic force microscopy. The CPDs-PNM exhibited high photothermal conversion efficiency, lower critical solution temperature (LCST) behavior, and good cytarabine (arabinosyl cytosine, AraC) loading capacity (62.3%). The formation of a CPDs-PNM/AraC adduct and photothermal-controlled drug release, triggered by green light excitation, were demonstrated by spectroscopic techniques, and the drug-polymer interaction and drug release mechanism were well supported by modeling simulation calculations. The cellular uptake of empty and AraC-loaded CPDs-PNM was imaged by confocal laser scanning microscopy. In vitro experiments evidenced that CPDs-PNM did not affect the viability of neuroblastoma cells, while the CPDs-PNM/AraC adduct under light irradiation exhibited significantly higher toxicity than AraC alone by a combined chemo-photothermal effect.


Assuntos
Hipertermia Induzida , Nanopartículas , Carbono/química , Doxorrubicina/química , Citarabina , Polímeros/química , Luz , Fototerapia/métodos , Nanopartículas/química
4.
Ann Hematol ; 102(2): 329-335, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36633637

RESUMO

A standard salvage regimen for patients with acute myeloid leukemia (AML) who are not in complete remission (CR) after initial induction therapy does not exist. We retrospectively investigated re-induction therapy for 151 patients with AML who did not achieve CR after the initial course between January 2014 and March 2021. The re-induction regimen did not correlate with the CR rate after the second course, whereas patients had similar 5-year overall survival (OS) and event-free survival (EFS) based on different re-induction regimens. Multivariable analysis revealed that International European Leukaemia Net (ELN) risk stratification independently predicted both OS and EFS among patients not in CR after the first course, although the re-induction regimen did not predict prognosis. Urgent salvage alloHSCT may improve the prognosis of patients with refractory AML. In summary, our study showed that the re-induction regimen did not significantly predict the prognosis of patients with AML not in CR after the first course of treatment. The development and selection of an efficient treatment algorithm for the treatment of AML remains a pressing research challenge.


Assuntos
Quimioterapia de Indução , Leucemia Mieloide Aguda , Humanos , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina , Leucemia Mieloide Aguda/tratamento farmacológico , Indução de Remissão , Prognóstico
5.
Med Oncol ; 40(2): 77, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36625951

RESUMO

Chemotherapy followed by donor lymphocyte infusion (DLI) is a promising treatment for relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the best strategy for administering this therapy is still unclear. This study sought to explore the efficacy and safety of chidamide and CAG (cytarabine, aclarubicin, and granulocyte colony-stimulating factor) (CCAG) regimen followed by DLI in relapsed AML/MDS after allo-HSCT. This was a single-arm, phase II trial in patients with relapsed AML/MDS after allo-HSCT. CCAG regimen followed by DLI was given according to the inclusion and exclusion criteria. Twenty adult patients were enrolled. The median follow-up time was 12 months. The complete remission (CR) rate was 45% and the partial remission (PR) rate was 5%. The 1-year overall survival (OS) was 56.7% (95% confidence interval (95% CI), 31.6-75.6%), and the median OS was 19 months. The 1-year relapse-free survival (RFS) was 83.3% (95% CI, 27.3-97.5%). Patients relapsing more than 6 months after HSCT and achieving CR/PR after CCAG plus DLI regimen attained significantly higher survival rates. The cumulative incidence of grade III-IV acute graft-versus-host disease (aGVHD) was 9.4%. There was no treatment-related mortality (TRM). These data suggest that CCAG plus DLI regimen is safe and induces durable remission and superior survival in patients with relapsed AML/MDS after allo-HSCT. Trial registration number: ChiCTR.org identifier: ChiCTR1800017740 and date of registration: August 12, 2018.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Adulto , Humanos , Aclarubicina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Citarabina/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Síndromes Mielodisplásicas/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos , Linfócitos , Recidiva , Doença Enxerto-Hospedeiro/etiologia
6.
BMC Health Serv Res ; 23(1): 36, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36642712

RESUMO

BACKGROUND: Based on the results from the ALFA-0701 study, gemtuzumab ozogamicin (GO) has been approved by the European Medicine Agency and by the Italian Drug Agency for the first line treatment of de novo acute-myeloid leukemia (AML). In this analysis, we assessed the cost-effectiveness of GO in combination with daunorubicin and cytarabine (DA), vs DA alone, adopting the perspective of the Italian National Health Service. METHODS: For this analysis, a cohort state transition model was developed. The model was designed to capture health states and events that occur throughout the entire disease course and that impact costs and outcomes. The ALFA-0701 study was the main source of clinical data for this analysis. In the model, patients had the same baseline characteristics and experienced the same clinical improvements as in the ALFA-0701 study. Economic data (resource consumption and unit costs) were adapted to reflect expenditure for the Italian National Health Service. Utilities per health state and disutilities due to adverse events were based on the literature and on the general population for those functionally cured. A lifetime horizon was adopted, with both costs and outcome being discounted of 3.0%, annually. Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of results. RESULTS: In the base case (lifetime horizon; primary source of data: study ALFA-0701; perspective: Italian National Health Service; discount rate on costs and outcomes: 3.0%), GO + DA was more effective DA both in terms of life-year (LY) survival (6.42 LY vs 5.75 LY, respectively) and quality-of-life adjusted survival (4.69 QALY vs 4.19 QALY, respectively). The overall costs were almost similar in the two groups (slightly lower with GO + DA than with DA; €162,424 and €162,708, respectively). The use of GO increased the costs of drug therapy but saved costs of relapse and costs associated with transplantation (HSCT). CONCLUSIONS: If results of the ALFA-0701 study are applied to the Italian healthcare environment, then gemtuzumab ozogamicin, in combination with daunorubicin and cytarabine, would clinical outcomes and reduce lifetime costs, compared with daunorubicin and cytarabine alone for the first line treatment of de novo AML. TRIAL REGISTRATION: Not applicable.


Assuntos
Leucemia Mieloide Aguda , Humanos , Gemtuzumab/uso terapêutico , Medicina Estatal , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/etiologia , Daunorrubicina/uso terapêutico , Citarabina/uso terapêutico , Itália , Resultado do Tratamento , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/uso terapêutico
7.
J Biol Chem ; 299(1): 102798, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36528059

RESUMO

Chemotherapy resistance is the dominant challenge in the treatment of acute myeloid leukemia (AML). Nuclear factor E2-related factor 2 (Nrf2) exerts a vital function in drug resistance of many tumors. Nevertheless, the potential molecular mechanism of Nrf2 regulating the base excision repair pathway that mediates AML chemotherapy resistance remains unclear. Here, in clinical samples, we found that the high expression of Nrf2 and base excision repair pathway gene encoding 8-hydroxyguanine DNA glycosidase (OGG1) was associated with AML disease progression. In vitro, Nrf2 and OGG1 were highly expressed in drug-resistant leukemia cells. Upregulation of Nrf2 in leukemia cells by lentivirus transfection could decrease the sensitivity of leukemia cells to cytarabine, whereas downregulation of Nrf2 in drug-resistant cells could enhance leukemia cell chemosensitivity. Meanwhile, we found that Nrf2 could positively regulate OGG1 expression in leukemia cells. Our chromatin immunoprecipitation assay revealed that Nrf2 could bind to the promoter of OGG1. Furthermore, the use of OGG1 inhibitor TH5487 could partially reverse the inhibitory effect of upregulated Nrf2 on leukemia cell apoptosis. In vivo, downregulation of Nrf2 could increase the sensitivity of leukemia cell to cytarabine and decrease OGG1 expression. Mechanistically, Nrf2-OGG1 axis-mediated AML resistance might be achieved by activating the AKT signaling pathway to regulate downstream apoptotic proteins. Thus, this study reveals a novel mechanism of Nrf2-promoting drug resistance in leukemia, which may provide a potential therapeutic target for the treatment of drug-resistant/refractory leukemia.


Assuntos
Citarabina , DNA Glicosilases , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Apoptose , Núcleo Celular/metabolismo , Citarabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , DNA Glicosilases/metabolismo
8.
ACS Appl Mater Interfaces ; 15(1): 452-468, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36538368

RESUMO

Pyroptosis, as a novel mode of cell death, has been proven to have impressive antitumor effects. Dying cells undergoing pyroptosis can elicit antitumor immunity by the release of tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs). Accordingly, developing an effective, stable, and controllable nanoplatform that can promote these two side effects is a promising option for cancer therapy. In this study, we designed a carrier-free chemo-photodynamic nanoplatform (A-C/NPs) using a co-assembly strategy with cytarabine (Ara-C) and chlorin e6 (Ce6) to induce pyroptosis and a subsequent immune response against breast cancer. Mechanistically, A-C/NPs can trigger GSDME-mediated pyroptosis in a controllable manner through reactive oxygen species (ROS) accumulation, causing immunogenic cell death (ICD), in which dying cells release high-mobility group box 1 (HMGB1), adenosine triphosphate (ATP), and calcitonin (CRT). Additionally, Ara-C can stimulate the maturation of cytotoxic T lymphocytes to act synergistically with Ce6-mediated immunogenic cell death (ICD), collectively augmenting the anticancer effect of A-C/NPs. The A-C/NPs showed excellent suppressive effects on the growth of orthotopic, abscopal, and recurrent tumors in a breast cancer mouse model. The chemo-photodynamic therapy (PDT) using the proposed nanomedicine strategy could be a novel strategy for triggering pyroptosis and improving the global anticancer immune response.


Assuntos
Nanopartículas , Neoplasias , Fotoquimioterapia , Animais , Camundongos , Fármacos Fotossensibilizantes/farmacologia , Piroptose , Citarabina , Imunidade , Linhagem Celular Tumoral
9.
Curr Treat Options Oncol ; 23(12): 1829-1844, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36510037

RESUMO

OPINION STATEMENT: Improvements in systemic therapy in the treatment of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) have improved patient outcomes and reduced the incidence of CNS relapse. However, management of patients with CNS disease remains challenging, and relapses in the CNS can be difficult to salvage. In addition to treatment with CNS-penetrant systemic therapy (high-dose methotrexate and cytarabine), intrathecal prophylaxis is indicated in all patients with ALL, however is not uniformly administered in patients with AML without high-risk features. There is a limited role for radiation treatment in CNS prophylaxis; however, radiation should be considered for consolidative treatment in patients with CNS disease, or as an option for palliation of symptoms. Re-examining the role of established treatment paradigms and investigating the role of radiation as bridging therapy in the era of cellular therapy, particularly in chemotherapy refractory patients, is warranted.


Assuntos
Neoplasias do Sistema Nervoso Central , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Citarabina/uso terapêutico , Metotrexato/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central/etiologia , Neoplasias do Sistema Nervoso Central/prevenção & controle
10.
J Exp Clin Cancer Res ; 41(1): 340, 2022 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-36482393

RESUMO

BACKGROUND: Acute myeloid leukemia (AML) is an aggressive hematological cancer resulting from uncontrolled proliferation of differentiation-blocked myeloid cells. Seventy percent of AML patients are currently not cured with available treatments, highlighting the need of novel therapeutic strategies. A promising target in AML is the mammalian target of rapamycin complex 1 (mTORC1). Clinical inhibition of mTORC1 is limited by its reactivation through compensatory and regulatory feedback loops. Here, we explored a strategy to curtail these drawbacks through inhibition of an important effector of the mTORC1signaling pathway, the eukaryotic initiation factor 4A (eIF4A). METHODS: We tested the anti-leukemic effect of a potent and specific eIF4A inhibitor (eIF4Ai), CR-1-31-B, in combination with cytosine arabinoside (araC) or the BCL2 inhibitor venetoclax. We utilized the MOLM-14 human AML cell line to model chemoresistant disease both in vitro and in vivo. In eIF4Ai-treated cells, we assessed for changes in survival, apoptotic priming, de novo protein synthesis, targeted intracellular metabolite content, bioenergetic profile, mitochondrial reactive oxygen species (mtROS) and mitochondrial membrane potential (MMP). RESULTS: eIF4Ai exhibits anti-leukemia activity in vivo while sparing non-malignant myeloid cells. In vitro, eIF4Ai synergizes with two therapeutic agents in AML, araC and venetoclax. EIF4Ai reduces mitochondrial membrane potential (MMP) and the rate of ATP synthesis from mitochondrial respiration and glycolysis. Furthermore, eIF4i enhanced apoptotic priming while reducing the expression levels of the antiapoptotic factors BCL2, BCL-XL and MCL1. Concomitantly, eIF4Ai decreases intracellular levels of specific metabolic intermediates of the tricarboxylic acid cycle (TCA cycle) and glucose metabolism, while enhancing mtROS. In vitro redox stress contributes to eIF4Ai cytotoxicity, as treatment with a ROS scavenger partially rescued the viability of eIF4A inhibition. CONCLUSIONS: We discovered that chemoresistant MOLM-14 cells rely on eIF4A-dependent cap translation for survival in vitro and in vivo. EIF4A drives an intrinsic metabolic program sustaining bioenergetic and redox homeostasis and regulates the expression of anti-apoptotic proteins. Overall, our work suggests that eIF4A-dependent cap translation contributes to adaptive processes involved in resistance to relevant therapeutic agents in AML.


Assuntos
Antineoplásicos , Citarabina , Fator de Iniciação 4A em Eucariotos , Leucemia Mieloide Aguda , Humanos , Citarabina/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2 , Linhagem Celular Tumoral , Fator de Iniciação 4A em Eucariotos/antagonistas & inibidores , Antineoplásicos/farmacologia
11.
Best Pract Res Clin Haematol ; 35(4): 101408, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36517130

RESUMO

The safe diminution of leukemic cell numbers to a level such that the patient will not succumb to their disease has been an achievable, yet often elusive goal in AML. Disease heterogeneity based both on biological features as well as on patient characteristics such as age, exposure to prior to anti-cancer chemotherapy and co-morbidities play a role in an allowing the physician to predict which patient has a greater or lesser chance to be cured after a diagnosis of acute myeloid leukemia. Cure rates range from 95% in younger patients with non-high-risk acute promyelocytic leukemia to essentially zero in older adults with intrinsically resistant biologies such as complex karyotype and/or TP53 mutations. One unifying feature of all AMLs, however, is the notion that whatever initial therapy is used, while possible to eradicate all morphological evidence of disease in a sizeable fraction of patients, an initial cycle (or two) is not sufficient to yield a low enough disease burden to prevent eventual relapse. Thus, the application of additional chemotherapy after the initial complete remission is received (post-remission therapy generally or consolidation therapy if a myelointense approach is used) is absolutely required for the patient to have a reasonable chance at cure. The widely accepted principle of the need to provide post-remission therapy leads to multiple controversies pertaining to the appropriate intensity, drug choice, and duration of exposure to consolidation chemotherapy, which can range from repetitive cycles of non-intensive therapy, up to and including a myeloblative allogeneic stem cell transplant. In this review, both the principles and the individual strategies that can be used once remission is achieved, will be examined.


Assuntos
Quimioterapia de Consolidação , Leucemia Mieloide Aguda , Humanos , Idoso , Citarabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Indução de Remissão , Transplante de Células-Tronco , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
12.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 30(6): 1724-1729, 2022 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-36476895

RESUMO

OBJECTIVE: To investigate the effect and mechanism of artesunate (ARTS) combined with cytarabine(Ara-C) and/or daunorubicin (DNR) on the proliferation and apoptosis of MV4-11 human mixed-lineage leukemia rearranged(MLL-r) acute myeloid leukemia (AML) cell line. METHODS: CCK-8 assay was used to detect the proliferation effect of individual or in combination of ARTS, DNR, Ara-C on MV4-11 cells. The IC50 of ARTS, DNR and Ara-C was calculated separately. The cell apoptosis and expression of receptors DR4 and DR5 were detected by flow cytometry. Western blot was used to detect the expression of Caspase-3 and Caspase-9 in each groups. RESULTS: The inhibition effect of ARTS, Ara-C and DNR on the proliferation of MV4-11 were all dose-dependently (r=0.99, 0.90 and 0.97, respectively). The IC50 of ARTS, Ara-C and DNR on MV4-11 for 48 hours were 0.31 µg/ml, 1.43 µmol/L and 22.47 nmol/L, respectively. At the dose of ARTS 0.3 µg/ml, Ara-C 1.0 µmol/L and DNR 15 nmol/L, the proliferation rate for 48 hours of the tri-combination treatment was significantly lower than that of the bi-combination treatment, while both were significantly lower than that of the individual treatment (all P<0.05). In terms of bi-combination treatment, the cells proliferation rate for 48 hours of the ARTS+Ara-C group was significantly lower than that of the ARTS+DNR group, while both were significantly lower than that of the Ara-C+DNR group (all P<0.05). The cooperativity index (CI) of bi- and tri-combination treatment were all less than 1. After 48 hours of drug action, the cell apoptosis rate of the ARTS+DNR+Ara-C group was significantly higher than that of the Ara-C+DNR group, while both were significantly higher than that of the ARTS+DNR group (all P<0.05). Meanwhile, the was no statistical difference between the cells apoptotic rate of the ARTS+DNR+Ara-C group and the ARTS+Ara-C group (P>0.05). The expression of DR4 and DR5 also showed no difference between control group and drug group. Compared with the DNR+Ara-C group, the expressions of Caspase-3 were significantly down-regulated in both the ARTS+DNR+Ara-C group and the ARTS+Ara-C group (all P<0.05). The down-regulation of Caspase-3 expression was the most significantly in the combination group of three drugs, while the Caspase-9 expressions in different groups showed no apparent change. CONCLUSION: The in vitro study showed that tri-combination of ARTS+Ara-C+DNR and bi-combination of ARTS+Ara-C could inhibit the proliferation and promote apoptosis of MV4-11 cell line. The inhibition effect of these two combinations were significantly superior to that of the traditional Ara-C+DNR treatment. The mechanism underlying this finding may be identified by the down regulation of Caspase-3, while no altered expression was observed of Caspase-9, DR4 and DR5.


Assuntos
Citarabina , Leucemia Mieloide Aguda , Humanos , Citarabina/farmacologia , Daunorrubicina/farmacologia , Caspase 3 , Caspase 9 , Artesunato/farmacologia , Apoptose , Linhagem Celular
13.
Hematology Am Soc Hematol Educ Program ; 2022(1): 23-29, 2022 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-36485116

RESUMO

Acute myeloid leukemia (AML) secondary to antecedent hematologic disorder or prior therapeutics for cancer represent a diverse group of leukemias often associated with inferior outcomes. Conventional therapy with cytarabine-based chemotherapy has been the mainstay of care for the past 30 years with disappointing overall outcomes. Novel therapies, including liposomal cytarabine/daunorubicin, and venetoclax-based therapies have emerged as options in recent years based on studies showing improvement in outcomes over standard-of-care therapies. Despite these advances, mutations in TP53 are associated with inferior response to both therapies and represent an area of unmet clinical need. Novel strategies with immune-targeted therapies such as CD47 monoclonal antibodies appear active in early-phase studies, but randomized studies have yet to report outcomes leading to approval. Allogeneic transplant remains the only known curative therapy for many of these cases. Nonetheless, pretransplant high-risk molecular features of secondary AML are associated with inferior outcome despite transplantation. An optimal approach to secondary AML is yet to be determined.


Assuntos
Leucemia Mieloide Aguda , Segunda Neoplasia Primária , Humanos , Daunorrubicina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamento farmacológico , Citarabina/uso terapêutico
14.
Sci Rep ; 12(1): 21541, 2022 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-36513674

RESUMO

Induction chemotherapy based on high-dose methotrexate is considered as the standard approach for newly diagnosed primary central nervous system lymphomas (PCNSLs). However, the best combination chemotherapeutic regimen remains unclear. This study aimed to determine the efficacy and toxicities of rituximab with methotrexate (R-M regimen). Consecutive 37 Chinese patients receiving R-M regimen as induction chemotherapy were retrospectively identified from January 2015 to June 2020 from our center in eastern China. Fourteen patients receiving rituximab plus methotrexate with cytarabine (R-MA regimen) at the same period were identified as the positive control group. The response rates, survival, toxicities, length of hospital stay (LOS), and cost were compared. Compared with the R-MA regimen, the R-M regimen showed comparable response rate and survival outcomes, but had fewer grade 3-4 hematological toxicities, shorter LOS, lower mean total hospitalization cost and lower mean total antibiotic cost. Complete remission at the end of induction chemotherapy and ECOG > 3 were independent prognostic factors for overall survival. In conclusion, R-M regimen is an effective and cost-effective combination treatment for PCNSLs, which warrants further evaluation in randomized trials.


Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma , Humanos , Rituximab/efeitos adversos , Metotrexato/efeitos adversos , Neoplasias do Sistema Nervoso Central/diagnóstico , Linfoma/diagnóstico , Estudos Retrospectivos , Análise Custo-Benefício , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/efeitos adversos , Resultado do Tratamento , Sistema Nervoso Central
15.
Int J Pharm ; 629: 122386, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36372139

RESUMO

In order to highlight the advantages of cocrystallization technique in perfecting in vitro/vivo natures of marine drug cytarabine (ARC), and fill the gap of the research of marine pharmaceutical cocrystals with synergistic antitumor effects, the first dual-drug cocrystal simultaneously containing ARC and antitumor drug 5-fluorouracil (FU), viz. ARC-FU, is successfully designed and assembled. The accurate structure is perfectly resolved by single-crystal X-ray diffraction and other approaches. The analytical outcomes demonstrate that the codrug cocrystal consists of ARC and FU with a molar ratio of 1:1, in which FU molecule plays an important role by participating in the formation of both "pyrimidine-pyrimidine" and "pyrimidine-sugar" cyclic hydrogen-bonding systems with ARC molecules. In the cocrystal, there are twofold hydrogen-bonding helixes of ARC molecules and a whole three-dimensional hydrogen-bonding network which also contains the aromatic stacking interaction between pyrimidine rings of both components. Such structural feature and aggregation model have crucial influences on the improvements of in vitro/vivo properties, which is methodically verified by the combination of theoretical analyses and experimental measurements. The in vitro studies exhibit the suitably reduced solubility and obviously increased permeability for the cocrystal that is in accord with the theoretical prediction. Importantly, the ameliorated in vitro peculiarities realize in vivo pharmacokinetic optimization including the extended residence time and enhanced relative bioavailability. Of greater significance, ARC exerts synergistic antitumor effects in association with FU that brings about potentiation of cell growth inhibition with lower IC50. Thus, this research not only provides a novel crystalline form for ARC with forward-looking development value, but also breaks new ground for the development of synergistic antitumor pharmaceutical cocrystals with marine characteristics.


Assuntos
Produtos Biológicos , Fluoruracila , Preparações Farmacêuticas/química , Fluoruracila/farmacologia , Fluoruracila/química , Citarabina/farmacologia , Cristalização , Solubilidade , Administração Oral , Hidrogênio
16.
BMC Genomics ; 23(1): 752, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36376859

RESUMO

BACKGROUND: Elucidation of the genetic mechanisms underlying treatment response to standard induction chemotherapy in AML patients is warranted, in order to aid in risk-adapted treatment decisions as novel treatments are emerging. In this pilot study, we explored the treatment-induced expression patterns in a small cohort of AML patients by analyzing differential gene expression (DGE) over the first 2 days of induction chemotherapy. METHODS: Blood samples were collected from ten AML patients at baseline (before treatment initiation) and during the first 2 days of treatment (Day 1; approximately 24 h, and Day 2; approximately 48 h after treatment initiation, respectively) and RNA was extracted for subsequent RNA sequencing. DGE between time points were assessed by pairwise analysis using the R package edgeR version 3.18.1 in all patients as well as in relation to treatment response (complete remission, CR, vs non-complete remission, nCR). Ingenuity Pathway Analysis (Qiagen) software was used for pathway analysis and visualization. RESULTS: After initial data quality control, two patients were excluded from further analysis, resulting in a final cohort of eight patients with data from all three timepoints. DGE analysis demonstrated activation of pathways with genes directly or indirectly associated with NF-κB signaling. Significant activation of the NF-κB pathway was seen in 50% of the patients 2 days after treatment start, while iNOS pathway effects could be identified already after 1 day. nCR patients displayed activation of pathways associated with cell cycle progression, oncogenesis and anti-apoptotic behavior, including the STAT3 pathway and Salvage pathways of pyrimidine ribonucleotides. Notably, a significant induction of cytidine deaminase, an enzyme responsible for the deamination of Ara-C, could be observed between baseline and Day 2 in the nCR patients but not in patients achieving CR. CONCLUSIONS: In conclusion, we show that time-course analysis of gene expression represents a feasible approach to identify relevant pathways affected by standard induction chemotherapy in AML patients. This poses as a potential method for elucidating new drug targets and biomarkers for categorizing disease aggressiveness and evaluating treatment response. However, more studies on larger cohorts are warranted to elucidate the transcriptional basis for drug response.


Assuntos
Quimioterapia de Indução , Leucemia Mieloide Aguda , Humanos , NF-kappa B/genética , Transcriptoma , Projetos Piloto , Citarabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética
17.
BMC Cancer ; 22(1): 1174, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36376888

RESUMO

BACKGROUND: For patients with acute myeloid leukaemia (AML), the only potentially curative treatment is intensive chemotherapy (IC). This is highly toxic, particularly for patients > 60 years, potentially leading to prolonged hospitalisations requiring intensive supportive care, and sometimes treatment-related death. This also results in extensive healthcare costs and negatively impacts quality of life (QoL). Venetoclax with low-dose cytarabine (VEN + LDAC) is a novel, low-intensity treatment for AML patients who cannot receive IC. VEN + LDAC is given as an outpatient and toxicity appears significantly lower than with IC. Analysis of clinical trials performed to date are promising for patients with the genotype NPM1mutFLT3 ITDneg, where remission and survival rates appear comparable to those achieved with IC. METHODS: VICTOR is an international, two-arm, open-label, multi-centre, non-inferiority, randomised-controlled phase II trial to assess VEN + LDAC compared to standard of care (IC) as first-line treatment in older patients (initially aged ≥ 60 years) with newly diagnosed AML. The trial will recruit patients with a NPM1mutFLT3 ITDneg genotype; those with a favourable risk in relation to the experimental treatment. University of Birmingham is the UK co-ordinating centre, with national hubs in Aarhus University Hospital, Denmark, and Auckland District Health Board, New Zealand. The primary outcome is molecular event-free survival time where an event is defined as failure to achieve morphological complete response (CR) or CR with incomplete blood count recovery after two cycles of therapy; molecular persistence, progression or relapse requiring treatment change; morphological relapse, or; death. Secondary outcomes include cumulative resource use at 12- and 24-months, and QoL as assessed by EORTCQLQ-C30 and EQ-5D-3L at 3-, 6-, 12-, 18- and 24-months. The trial employs an innovative Bayesian design with target sample size of 156 patients aged > 60 years. DISCUSSION: The principle underpinning the VICTOR trial is that the chance of cure for patients in the experimental arm should not be compromised, therefore, an adaptive design with regular checks on accumulating data has been employed, which will allow for a staged expansion of the trial population to include younger patients if, and when, there is sufficient evidence of non-inferiority in older patients. TRIAL REGISTRATION: EudraCT: 2020-000,273-24; 21-Aug-2020. ISRCTN: 15,567,173; 08-Dec-2020.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Adulto , Idoso , Citarabina , Qualidade de Vida , Teorema de Bayes , Padrão de Cuidado , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Antineoplásicos/uso terapêutico , Proteínas Nucleares , Ensaios Clínicos Fase II como Assunto , Estudos Multicêntricos como Assunto
18.
J Investig Med High Impact Case Rep ; 10: 23247096221127114, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36341907

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive malignancy with poor outcomes. Although novel options like tagraxofusp, a CD123-directed cytotoxin, has emerged and is promising, treatment options are very limited in the relapsed and recurrent setting. We present a case of refractory BPDCN in a 62-year-old man who showed a complete bone marrow response to liposomal daunorubicin and cytarabine (vyxeos).


Assuntos
Neoplasias Hematológicas , Transtornos Mieloproliferativos , Neoplasias Cutâneas , Masculino , Humanos , Pessoa de Meia-Idade , Neoplasias Hematológicas/patologia , Citarabina , Células Dendríticas/patologia , Neoplasias Cutâneas/patologia , Daunorrubicina , Doença Aguda
19.
Rinsho Ketsueki ; 63(10): 1397-1401, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-36351646

RESUMO

NUP98::DDX10 is a rare fusion gene associated with acute myeloid leukemia (AML), for which the prognosis and indication for allogeneic hematopoietic stem cell transplantation are unknown. A 48-year-old woman was diagnosed with AML harboring NUP98::DDX10. The results of quantitative RT-PCR of the fusion mRNA as a minimal residual disease (MRD) marker guided the treatment. In August 2019, the patient achieved hematological remission following standard remission induction therapy with idarubicin and cytarabine. After four cycles of consolidation therapies, MRD was detected, and she underwent allogeneic stem cell transplantation in May 2020. As MRD persisted in June, the immunosuppressant was stopped and three cycles of azacitidine were administered. Despite this, a hematological relapse occurred in January 2021 that was resistant to high-dose cytarabine and an investigational agent. She died as a result of the disease's progression. Thus, a second thought should be given to the timing of transplantation, the bridging, and the intervention for relapse after transplantation. The cases must be accumulated.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Feminino , Humanos , Pessoa de Meia-Idade , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamento farmacológico , Citarabina/uso terapêutico , Neoplasia Residual , Prognóstico , Recidiva , Complexo de Proteínas Formadoras de Poros Nucleares/genética , RNA Helicases DEAD-box/genética
20.
Sci Rep ; 12(1): 18461, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36323739

RESUMO

DNA polymerase η (polη) is of significant value for designing new families of anticancer drugs. This protein takes a role in many stages of the cell cycle, including DNA replication, translesion DNA synthesis, and the repairing process of DNA. According to many studies, a high level of expression of polη in most cases has been associated with low rates of patients' survival, regardless of considering the stage of tumor cells. Thus, the design of new drugs with fewer side effects to inhibit polη in cancerous cells has attracted attention in recent years. This project aims to design and explore the alternative inhibitors for polη, which are based on carbohydrates and amino acids. In terms of physicochemical properties, they are similar to the traditional anticancer drugs such as Cytarabine (cytosine arabinose). These alternative inhibitors are supposed to disrupt the DNA replication process in cancerous cells and prevent the tumor cells from mitosis. These newly designed structures, which are based on natural products, are expected to be non-toxic and to have the same chemotherapeutic impact as the traditional agents. The combinatorial use of quantum mechanics studies and molecular dynamic simulation has enabled us to precisely predict the inhibition mechanism of the newly designed structure, which is based on carbohydrates and amino acids, and compare it with that of the traditional chemotherapeutic drugs such as Cytarabine. Our results suggest that the inhibitors containing the natural building blocks of amino acid and carbohydrate could be considered alternative drugs for Cytarabine to block polη.


Assuntos
Aminoácidos , Antineoplásicos , Humanos , Aminoácidos/genética , Replicação do DNA , Citarabina/farmacologia , Citarabina/química , Antineoplásicos/farmacologia , Dano ao DNA , DNA/metabolismo , Carboidratos
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