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1.
BMC Cancer ; 22(1): 1254, 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36460969

RESUMO

The integrated stress response (ISR) facilitates cellular adaptation to unfavorable conditions by reprogramming the cellular response. ISR activation was reported in neurological disorders and solid tumors; however, the function of ISR and its role as a possible therapeutic target in hematological malignancies still remain largely unexplored. Previously, we showed that the ISR is activated in chronic myeloid leukemia (CML) cells and correlates with blastic transformation and tyrosine kinase inhibitor (TKI) resistance. Moreover, the ISR was additionally activated in response to imatinib as a type of protective internal signaling. Here, we show that ISR inhibition combined with imatinib treatment sensitized and more effectively eradicated leukemic cells both in vitro and in vivo compared to treatment with single agents. The combined treatment specifically inhibited the STAT5 and RAS/RAF/MEK/ERK pathways, which are recognized as drivers of resistance. Mechanistically, this drug combination attenuated both interacting signaling networks, leading to BCR-ABL1- and ISR-dependent STAT5 activation. Consequently, leukemia engraftment in patient-derived xenograft mice bearing CD34+ TKI-resistant CML blasts carrying PTPN11 mutation responsible for hyperactivation of the RAS/RAF/MAPK and JAK/STAT5 pathways was decreased upon double treatment. This correlated with the downregulation of genes related to the RAS/RAF/MAPK, JAK/STAT5 and stress response pathways and was associated with lower expression of STAT5-target genes regulating proliferation, viability and the stress response. Collectively, these findings highlight the effect of imatinib plus ISRIB in the eradication of leukemic cells resistant to TKIs and suggest potential clinical benefits for leukemia patients with TKI resistance related to RAS/RAF/MAPK or STAT5 signaling. We propose that personalized treatment based on the genetic selection of patients carrying mutations that cause overactivation of the targeted pathways and therefore make their sensitivity to such treatment probable should be considered as a possible future direction in leukemia treatment.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide , Humanos , Animais , Camundongos , Fator de Transcrição STAT5/genética , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Transdução de Sinais , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
2.
Blood ; 121(20): 4175-83, 2013 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-23543457

RESUMO

Genomic instability is a hallmark of chronic myeloid leukemia in chronic phase (CML-CP) resulting in BCR-ABL1 mutations encoding resistance to tyrosine kinase inhibitors (TKIs) and/or additional chromosomal aberrations leading to disease relapse and/or malignant progression. TKI-naive and TKI-treated leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) accumulate high levels of reactive oxygen species (ROS) and oxidative DNA damage. To determine the role of TKI-refractory LSCs in genomic instability, we used a murine model of CML-CP where ROS-induced oxidative DNA damage was elevated in LSCs, including quiescent LSCs, but not in LPCs. ROS-induced oxidative DNA damage in LSCs caused clinically relevant genomic instability in CML-CP-like mice, such as TKI-resistant BCR-ABL1 mutations (E255K, T315I, H396P), deletions in Ikzf1 and Trp53, and additions in Zfp423 and Idh1. Despite inhibition of BCR-ABL1 kinase, imatinib did not downregulate ROS and oxidative DNA damage in TKI-refractory LSCs to the levels detected in normal cells, and CML-CP-like mice treated with imatinib continued to accumulate clinically relevant genetic aberrations. Inhibition of class I p21-activated protein kinases by IPA3 downregulated ROS in TKI-naive and TKI-treated LSCs. Altogether, we postulate that genomic instability may originate in the most primitive TKI-refractory LSCs in TKI-naive and TKI-treated patients.


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Instabilidade Genômica , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Células-Tronco Neoplásicas/fisiologia , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Animais , Células Cultivadas , Dano ao DNA/efeitos dos fármacos , Instabilidade Genômica/efeitos dos fármacos , Instabilidade Genômica/fisiologia , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Camundongos , Camundongos Transgênicos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo
3.
Eur J Haematol ; 91(1): 1-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23521128

RESUMO

OBJECTIVES: The relationship between treatments of chronic lymphocytic leukemia (CLL) with cladribine (2-CdA) or chlorambucil and immune thrombocytopenia (IT) has not been yet determined. METHODS: The records of 777 patients in two randomized Polish Adult Leukemia Group (PALG)-CLL programs treated with these agents were retrospectively analyzed. RESULTS: Immune thrombocytopenia occurred in 55 of 777 (7.1%) patients. No significant differences in IT prevalence were seen between patients on chlorambucil or 2-CdA-based regiments (P = 0.33). IT developed at a median time of 0.499 yr (0.06-4.8) from the start of CLL therapy. This time was significantly longer in patients treated with chlorambucil (2.03 yr, 95% CI: 0.06-4.22) in relation to patients treated with 2-CdA-based regiments (0.52 yr, 95%CI: 0.34-0.69, P = 0.049). Overall survival (OS) of patients with IT and those without IT were similar (2.65 yr vs. 3.2 yr P = 0.23) but the severity of bleeding was more pronounced in the 2-CdA group. The responses to IT therapy were 35%, 54% and 75% for steroids, chemotherapy and splenectomy, respectively. CONCLUSIONS: In this study, an unexpectedly high percentage of IT incidence was demonstrated in patients with CLL requiring chemotherapy. Although no marked differences were seen in IT frequency in patients treated with 2-CdA-based regiments compared to chlorambucil regimen, the clinical course of hemorrhagic diathesis was more severe in 2-CdA group. Also, the time elapsed from study screening to IT diagnosis was significantly shorter in the 2-CdA group than in the chlorambucil group suggesting a causative relationship. The appearance of IT did not influence the median time of OS.


Assuntos
Clorambucila/uso terapêutico , Cladribina/uso terapêutico , Leucemia Linfocítica Crônica de Células B/complicações , Trombocitopenia/complicações , Idoso , Feminino , Seguimentos , Hemorragia , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Trombocitopenia/imunologia , Trombocitopenia/terapia , Fatores de Tempo , Resultado do Tratamento
4.
J Cancer Res Clin Oncol ; 149(10): 7103-7112, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36871092

RESUMO

PURPOSE: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by recurrent genetic aberration in leukemic stem cells, namely Philadelphia chromosome caused by reciprocal translocation t(9;22)(q34;q11). In our study, we analyzed the telomeric complex expression and function in the molecular pathogenesis of CML. METHODS: We employed CD34+ primary leukemic cells, comprising both leukemic stem and progenitor cell populations, isolated from peripheral blood or bone marrow of CML patients in chronic and blastic phase to analyze the telomere length and telomeric-associated proteins. RESULTS: The reduction in telomere length during disease progression was correlated with increased expression of BCR::ABL1 transcript and the dynamic changes were neither associated with the enzymatic activity of telomerase nor with gene copy number and expression of telomerase subunits. Increased expression of BCR::ABL1 was positively correlated with expression of TRF2, RAP1, TPP1, DKC1, TNKS1, and TNKS2 genes. CONCLUSIONS: The dynamics of telomere length changes in CD34+ CML cells is dependent on the expression level of BCR::ABL, which promotes the expression of certain shelterins including RAP1 and TRF2, as well as TNKS, and TNKS2, and results in telomere shortening regardless of telomerase activity. Our results may allow better understanding of the mechanisms responsible for the genomic instability of leukemic cells and CML progression.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Tanquirases , Telomerase , Humanos , Medula Óssea/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteínas Nucleares/genética , Tanquirases/genética , Tanquirases/metabolismo , Telomerase/genética , Telomerase/metabolismo , Telômero/metabolismo
5.
Clin Lymphoma Myeloma Leuk ; 23(1): e19-e26, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36396583

RESUMO

INTRODUCTION: Ruxolitinib is widely used in myelofibrosis (MF). However, some patients do not optimally respond and require more efficacious treatment. Our analysis aimed to establish predictors of ruxolitinib response. PATIENTS AND METHODS: We designed a multicenter, retrospective analysis of the efficacy of ruxolitinib treatment in patients with MF in 15 Polish hematology centers. As responses to ruxolitinib occur within the first 6 months, we used this point to evaluate the efficacy of treatment. Symptoms response was defined as ≥50% reduction of the MF constitutional symptoms assessed by Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS). Spleen response was defined as ≥50% reduction of the difference between the spleen's baseline length and the upper limit norm measured by ultrasonography. RESULTS: 320 MF patients were enrolled. At 6 months of therapy, the spleen response was detected in 140 (50%) patients, and symptoms response in 241 patients (76%). Multivariable analysis identified leukocytosis <25 G/L (OR 2.06, 95%CI: 1.12-3.88, P = .0200), and reticulin fibrosis MF 1 (OR 2.22, 95%CI: 1.11-4.46, P = .0249) contributed to better spleen response. The time interval between MF diagnosis and ruxolitinib administration shorter than 3 months, and platelets ≥150 G/L (OR 1.69, 95% CI 1.01-2.83, P = .0466) influenced symptoms response. CONCLUSION: Establishing predictive factors for ruxolitinib response is particularly important given the potential for new therapies in MF. In patients with a low likelihood of responding to ruxolitinib, using other JAK inhibitors or adding a drug with a different mechanism of action to ruxolitinib may be of clinical benefit.


Assuntos
Leucemia , Mielofibrose Primária , Humanos , Adulto , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/tratamento farmacológico , Estudos Retrospectivos , Polônia , Sistema de Registros
6.
Blood Adv ; 6(17): 5171-5183, 2022 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-35802458

RESUMO

Myeloproliferative neoplasms (MPNs) are uncommon in children/young adults. Here, we present data on unselected patients diagnosed before 25 years of age included from 38 centers in 15 countries. Sequential patients were included. We identified 444 patients, with median follow-up 9.7 years (0-47.8). Forty-nine (11.1%) had a history of thrombosis at diagnosis, 49 new thrombotic events were recorded (1.16% patient per year [pt/y]), perihepatic vein thromboses were most frequent (47.6% venous events), and logistic regression identified JAK2V617F mutation (P = .016) and hyperviscosity symptoms (visual disturbances, dizziness, vertigo, headache) as risk factors (P = .040). New hemorrhagic events occurred in 44 patients (9.9%, 1.04% pt/y). Disease transformation occurred in 48 patients (10.9%, 1.13% pt/y), usually to myelofibrosis (7.5%) with splenomegaly as a novel risk factor for transformation in essential thrombocythemia (ET) (P= .000) in logistical regression. Eight deaths (1.8%) were recorded, 3 after allogeneic stem cell transplantation. Concerning conventional risk scores: International Prognostic Score for Essential Thrombocythemia-Thrombosis and new International Prognostic Score for Essential Thrombocythemia-Thrombosis differentiated ET patients in terms of thrombotic risk. Both scores identified high-risk patients with the same median thrombosis-free survival of 28.5 years. No contemporary scores were able to predict survival for young ET or polycythemia vera patients. Our data represents the largest real-world study of MPN patients age < 25 years at diagnosis. Rates of thrombotic events and transformation were higher than expected compared with the previous literature. Our study provides new and reliable information as a basis for prospective studies, trials, and development of harmonized international guidelines for the specific management of young patients with MPN.


Assuntos
Transtornos Mieloproliferativos , Policitemia Vera , Mielofibrose Primária , Trombocitemia Essencial , Trombose , Adulto , Criança , Humanos , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/epidemiologia , Policitemia Vera/complicações , Mielofibrose Primária/genética , Estudos Prospectivos , Trombose/etiologia , Adulto Jovem
7.
Hematol Oncol ; 28(2): 93-7, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19728396

RESUMO

A small subgroup of patients with hypereosinophilic syndrome (HES) demonstrates imatinib-sensitive fusion transcript-the FIP1L1-PDGFRA (F/P+). These cases are currently diagnosed as chronic eosinophilic leukaemia (CEL). In this paper, we screened 77 patients to estimate the frequency of FIP1L1-PDGFRA transcript among patients with unexplained, long-term hypereosinophilia exceeding 1.5 x 10(9)/L and to analyse the clinical and serological features in F/P+ CEL population. The FIP1L1-PDGFRA chimeric protein was detectable in 16 (14 males and 2 females) out of 77 examined HES patients (20%) by RT-PCR. Two patients suffered from cough at diagnosis. Three out of 16 (18%) patients had no organ involvements, in 5-one organ was affected and in the remaining eight cases-at least two. Eosinophilic organ damage/dysfunction identified splenomegaly in the majority of studied patients. We compared clinical and serological features between CEL F/P+ (n = 16) and HES (n = 61) patients. F/P+ cases had significantly increased WBC and absolute eosinophil count (AEC) at diagnosis (p = 0.008 and 0.02), whereas platelet count was decreased in this population (p = 0.03). Serum B12 and tryptase levels were increased (p = 0.002 and 0.004) in CEL F/P+ patients when compared to HES cases whereas serum IL-5 levels were significantly increased in the latter group (p = 0.01). Male gender and splenomegaly occurred more frequent in CEL F/P+ population (p = 0.002 and 0.0007, respectively). Additionally, patients with F/P+ CEL (n = 16) were compared with F/P- CEL (n = 8). The latter group, was significantly older, had lower AEC and higher platelet count. In conclusion, significant clinical symptoms are infrequent present and splenomegaly remains the most common organ involvement in patients with CEL expressing F/P fusion transcript. Our study confirmed the long-term remission on imatinib in this patient population.


Assuntos
Síndrome Hipereosinofílica/genética , Proteínas de Fusão Oncogênica/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Fatores de Poliadenilação e Clivagem de mRNA/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Tosse/etiologia , Feminino , Hepatomegalia/etiologia , Humanos , Síndrome Hipereosinofílica/sangue , Síndrome Hipereosinofílica/complicações , Síndrome Hipereosinofílica/tratamento farmacológico , Síndrome Hipereosinofílica/epidemiologia , Mesilato de Imatinib , Achados Incidentais , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Piperazinas/uso terapêutico , Contagem de Plaquetas , Polônia/epidemiologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , RNA Mensageiro/genética , RNA Neoplásico/genética , Esplenomegalia/etiologia , Adulto Jovem
9.
Br J Haematol ; 142(2): 227-37, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18492099

RESUMO

The treatment of adults with Philadelphia-negative acute lymphoblastic leukaemia (ALL) depends on the presence of risk factors including age, white blood cell count, immunophenotype and time to complete remission. In recent years, status of minimal residual disease (MRD) has been postulated as an additional risk criterion. This study prospectively evaluated the significance of MRD. Patients were treated with a uniform Polish Adult Leukemia Group (PALG) 4-2002 protocol. MRD status was assessed after induction and consolidation by multiparametric flow cytometry. Out of 132 patients included (age, 17-60 years), 116 patients were suitable for analysis. MRD level >/=0.1% of bone marrow cells after induction was found to be a strong and independent predictor for relapse in the whole study population (P < 0.0001), as well as in the standard risk (SR, P = 0.0003) and high-risk (P = 0.008) groups. The impact of MRD after consolidation on outcome was not significant. The combination of MRD status with conventional risk stratification system identified a subgroup of patients allocated to the SR group with MRD <0.1% after induction who had a very low risk of relapse of 9% at 3 years as opposed to 71% in the remaining subjects (P = 0.001). We conclude that MRD evaluation after induction should be considered with conventional risk criteria for treatment decisions in adult ALL.


Assuntos
Antígenos CD/análise , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Células da Medula Óssea/imunologia , Feminino , Citometria de Fluxo/métodos , Humanos , Imunofenotipagem/métodos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/imunologia , Polônia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Recidiva , Risco , Adulto Jovem
10.
Ann Transplant ; 12(3): 33-8, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18290568

RESUMO

BACKGROUND: We report a patient with acute promyelocytic leukemia (APL) relapse in extremely rare sites--the pleura, heart and pericardium without evidence of bone marrow infiltration and with molecular evidence of disease after allogeneic stem cell transplantation (alloSCT). CASE DESCRIPTION: Presented patient underwent alloSCT in second complete hematological and cytogenetic remission with presence of promyelocytic leukemia-retinoic acid receptor A (PML-RARA) detected in reverse transcription-polymerase chain reaction (RT-PCR) with sensitivity of 10(-2). After transplant, this patient remained in complete hematological and cytogenetic remission but nested RT-PCR assays with detection thresholds of 10(-3)/10(-4) were positive for PML-RARA rearranged gene even chimerism tests showed 100% of donor profile. He was in a very good clinical condition and presented symptoms of transient limited chronic graft vs. host disease. Twenty one months after transplant, the leukemic relapse in the pleura, heart and pericardium was diagnosed. At that time, PML-RARA transcript detected in RT-PCR assay (10(-2)) was positive for the first time after transplant. During salvage chemotherapy he died because of cardiogenic shock. CONCLUSIONS: We conclude that detection of PML-RARA after alloSCT should be indication insightful diagnosis of medullary or extramedullary (EM) relapse. The imaging techniques of all possible sites of APL EM relapse have to be included.


Assuntos
Neoplasias Cardíacas/diagnóstico , Leucemia Promielocítica Aguda/genética , Proteínas de Fusão Oncogênica/genética , Neoplasias Pleurais/diagnóstico , Sarcoma Mieloide/diagnóstico , Transplante de Células-Tronco , Adulto , Neoplasias Cardíacas/genética , Humanos , Leucemia Promielocítica Aguda/patologia , Leucemia Promielocítica Aguda/terapia , Masculino , Pericárdio , Neoplasias Pleurais/genética , Valor Preditivo dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sarcoma Mieloide/genética
11.
Med Oncol ; 34(6): 104, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28444623

RESUMO

Failure to comply with treatment recommendations is very common in patients, but still poorly recognised by doctors. The current practice of using oral therapy on a large scale has been increasingly adopted for cancer patients. Chronic myeloid leukaemia (CML) is just such an example, where the introduction of taking new oral medications, the tyrosine kinase BCR-ABL inhibitors (TKI), has now revolutionised the treatment. The aim of our study was to assess treatment adherence in a group of Polish CML patients (a survey was conducted on 140 patient aged ≥18 years) treated with oral TKI (imatinib, dasatinib and nilotinib) taking into account the following variables: gender, age, education, place of residence, family circumstances and duration of therapy. In addition, we evaluated whether there is a relationship between how patients perceive their level of adherence to treatment recommendations with how subjectively the required dosage regimen was followed. Half the patients admitted to skipping at least one drug dose during the entire course of treatment and 39% did so within their last treatment month. Patients were also found to overestimate their own adherence assessment; around 60% of those missing at least 1 drug dose within the last treatment month believed they 'always' followed recommendations. The study demonstrated that adherence deteriorates over time. Furthermore, patients aged >65 years and patients suffering at least one comorbid disease had better adherence (p < 0.011). There were no differences in adherence among patients treated with imatinib, dasatinib and nilotinib (p = 0.249).


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Adesão à Medicação/estatística & dados numéricos , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Antineoplásicos/uso terapêutico , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Tirosina Quinases , Inquéritos e Questionários
12.
J Clin Invest ; 127(6): 2392-2406, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28481221

RESUMO

Quiescent and proliferating leukemia cells accumulate highly lethal DNA double-strand breaks that are repaired by 2 major mechanisms: BRCA-dependent homologous recombination and DNA-dependent protein kinase-mediated (DNA-PK-mediated) nonhomologous end-joining, whereas DNA repair pathways mediated by poly(ADP)ribose polymerase 1 (PARP1) serve as backups. Here we have designed a personalized medicine approach called gene expression and mutation analysis (GEMA) to identify BRCA- and DNA-PK-deficient leukemias either directly, using reverse transcription-quantitative PCR, microarrays, and flow cytometry, or indirectly, by the presence of oncogenes such as BCR-ABL1. DNA-PK-deficient quiescent leukemia cells and BRCA/DNA-PK-deficient proliferating leukemia cells were sensitive to PARP1 inhibitors that were administered alone or in combination with current antileukemic drugs. In conclusion, GEMA-guided targeting of PARP1 resulted in dual cellular synthetic lethality in quiescent and proliferating immature leukemia cells, and is thus a potential approach to eradicate leukemia stem and progenitor cells that are responsible for initiation and manifestation of the disease. Further, an analysis of The Cancer Genome Atlas database indicated that this personalized medicine approach could also be applied to treat numerous solid tumors from individual patients.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células , Leucemia/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Cricetinae , Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades , Genes BRCA1 , Genes BRCA2 , Genes Letais , Genes abl , Humanos , Leucemia/tratamento farmacológico , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Células-Tronco Embrionárias Murinas/fisiologia , Ftalazinas/farmacologia , Piperazinas/farmacologia , Transcriptoma , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Ann Clin Microbiol Antimicrob ; 4: 8, 2005 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-15876349

RESUMO

BACKGROUND: Toxigenic strains of Corynebacterium diphtheriae are well known agent of diphtheria. Nontoxigenic strains can cause atypical course of the disease. Invasive diseases caused by C. diphtheriae occur very rare. CASE PRESENTATION: We have described the first case of septicemia and endocarditis due to nontoxigenic C. diphtheriae biotype gravis in Poland. The patient has not belonged to any group of risk such infection. CONCLUSION: The case presented in this article shows unusual case of infection connected with nontoxigenic C. diphtheriae that took place in the area where have been no cases of diphtheria and other C. diphtheriae infections for near ten years. It shows the importance of identifying Corynebacterium isolates at the species level especially when the strain has been isolated from normally sterile sites.


Assuntos
Bacteriemia/etiologia , Corynebacterium diphtheriae/isolamento & purificação , Endocardite Bacteriana/etiologia , Adulto , Corynebacterium diphtheriae/efeitos dos fármacos , Humanos , Masculino , Testes de Sensibilidade Microbiana
14.
Kardiol Pol ; 63(4): 414-8, 2005 Oct.
Artigo em Polonês | MEDLINE | ID: mdl-16273484

RESUMO

A case of a 59 year old male with infective endocarditis is presented. Antibiotic therapy seemed effective, however, inflammation laboratory parameters increased two weeks after clinical improvement and body temperature normalisation. Subsequent extensive laboratory investigations revealed multiple myeloma. The patient underwent successful aortic valve replacement and received pharmacological therapy for multiple myeloma. Difficulties in diagnosing and treatment of patients with infective endocarditis who have other concomitant diseases, are discussed.


Assuntos
Endocardite Bacteriana/diagnóstico , Endocardite Bacteriana/terapia , Valva Mitral/cirurgia , Mieloma Múltiplo/diagnóstico , Diagnóstico Diferencial , Endocardite Bacteriana/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Valva Mitral/microbiologia , Mieloma Múltiplo/complicações , Mieloma Múltiplo/terapia
17.
Exp Hematol ; 42(6): 439-47, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24667683

RESUMO

Despite undisputed success of tyrosine kinase inhibitors in the therapy of chronic myeloid leukemia (CML), development of drug resistance and inability to cure the disease challenge clinicians and researchers. Additionally, recent reports regarding cardiovascular toxicities of second and third generation tyrosine kinase inhibitors prove that there is still a place for novel therapeutic combinations in CML. We have previously shown that statins are able to modulate activity of chemotherapeutics or antibodies used in oncology. Therefore, we decided to verify that statins are able to potentiate antileukemic activity of imatinib, still a frontline treatment of CML. Lovastatin, a cholesterol lowering drug, synergistically potentiates antileukemic activity of imatinib in cell lines and in primary CD34+ CML cells from patients in different phases of the disease, including patients resistant to imatinib with no detectable mutations. This effect is related to increased intracellular concentration of imatinib in CD34+ CML cells and cell lines measured using uptake of (14)C-labeled imatinib. Lovastatin does not influence influx but significantly inhibits efflux of imatinib mediated by ATP-binding cassette (ABC) transporters: ABCB1 and ABCG2. The addition of cholesterol completely reverses these effects. Statins do not affect expression of ABCB1 and ABCG2 genes. The effects are drug-class specific, as observed with other statins. Our results suggest that statins may offer a valuable addition to imatinib in a select group of CML patients.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Leucemia Mieloide de Fase Crônica/fisiopatologia , Proteínas de Neoplasias/antagonistas & inibidores , Piperazinas/farmacologia , Pirimidinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Animais , Antineoplásicos/uso terapêutico , Western Blotting , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Mesilato de Imatinib , Células K562 , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/metabolismo , Lovastatina/farmacologia , Camundongos
18.
Exp Hematol ; 41(5): 462-9, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23395818

RESUMO

Chronic myelogenous leukemia (CML) is a stem cell disorder, and leukemia stem cells (LSCs) can contribute to the relapse of the disease. Quiescent LSCs are BCR-ABL independent and resistant to imatinib; therefore, there is an unmet need to identify new therapeutic targets in LSCs. Inhibition of the mammalian target of rapamycin (mTOR) in imatinib-resistant BCR-ABL1-positive cells was effective in vitro, but in a pilot clinical trial, only a few patients responded to the treatment. In this study, we demonstrate that mTOR activation in CML CD34(+) progenitor cells is ERK dependent in chronic phase of the disease and ERK independent in blast crisis. Rapamycin effectively inhibits mTOR in all phases of CML, but does not reduce number of LSC-enriched CD34(+) blast crisis (BC) cells, neither alone nor in combination with imatinib in CML-BC cells. These results show that potential therapeutic benefits of mTOR inhibition may be the result of effects on differentiated leukemic cells and may be potentially achieved only in the chronic phase of the disease.


Assuntos
Crise Blástica/enzimologia , Leucemia Mieloide de Fase Crônica/enzimologia , Células-Tronco Neoplásicas/enzimologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Crise Blástica/tratamento farmacológico , Crise Blástica/patologia , Western Blotting , Linhagem Celular , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Citometria de Fluxo , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Células K562 , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Células Tumorais Cultivadas
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