The Experts below are selected from a list of 315 Experts worldwide ranked by ideXlab platform
Nicholas C. Zoumbos - One of the best experts on this subject based on the ideXlab platform.
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c-Jun N-terminal kinase activation failure is a new mechanism of anthracycline resistance in acute myeloid leukemia.
Leukemia, 2008Co-Authors: Eleni D. Lagadinou, Panagiotis G. Ziros, Olga Tsopra, Kostas Dimas, Panagiotis Pantazis, Alexandros Spyridonidis, D Kokkinou, Eleni Thanopoulou, M. Karakantza, Nicholas C. ZoumbosAbstract:Chemotherapy resistance is a major challenge in acute myeloid leukemia (AML). Besides the P-glycoprotein efflux, additional cellular factors may contribute to drug resistance in AML. c-Jun N-terminal kinase (JNK) is activated after exposure of cells to chemotherapeutics. We asked whether chemoresistance in AML is attributed to intrinsic failure of the AML blasts to activate JNK. In vitro treatment of U937 AML cell line with anthracyclines induced a rapid and robust JNK phosphorylation and apoptosis. In contrast, the anthracyline-resistant derivative cell lines U937R and URD40 showed no JNK activation after exposure to anthracyclines, also at doses that resulted in high accumulation of the drug within the cells. RNA interference-based depletion of JNK1 in drug-sensitive U937 cells made them chemoresistant, whereas selective restoration of the inactive JNK pathway in the resistant U937R cells sensitized them to anthracyclines. Short-term in vitro exposure of primary AML cells (n=29) to daunorubicin showed a strong correlation between the in vitro pharmacodymanic changes of phospho-JNK levels and the response of patients to standard induction chemotherapy (P=0.012). We conclude that JNK activation failure confers another mechanism of anthracycline resistance in AML. Elucidating the ultimate mechanisms leading to JNK suppression in chemoresistant AML may be of major therapeutic value.
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c-Jun N-Terminal Kinase (JNK) Activation Failure Confers a New Mechanism of Anthracycline Resistance in Acute Myeloid Leukemia (AML).
Blood, 2007Co-Authors: Eleni D. Lagadinou, Panagiotis G. Ziros, Olga Tsopra, Kostas Dimas, Panagiotis Pantazis, Alexandros Spyridonidis, Nicholas C. ZoumbosAbstract:Chemotherapy resistance remains a major challenge in the treatment of acute myeloid leukemia (AML). Besides the P-glycoprotein efflux of chemotherapeutics, additional cellular factors may contribute to drug resistance in AML. c- Jun N-terminal Kinase (JNK) is a protein kinase activated after exposure of cells to chemotherapeutic agents. Recently, studies in solid tumours have associated chemoresistance with failure of cancer cells to activate JNK. We asked whether drug resistance in AML is also attributed to intrinsic failure of the AML blasts to activate JNK. In vitro treatment of U937 AML cell line with anthracyclines induced a rapid and robust JNK phosphorylation and apoptosis. In contrast, the anthracyline-resistant derivative U937R cells showed no JNK activation after exposure to anthracyclines, also at doses that resulted in high accumulation of the drug within the cells. Inhibition of JNK in drug-sensitive U937 cells made them resistant to anthracyclines. First, JNK1-siRNA transfected U937 cells exhibited a 50.4% and 61.3% reduced daunorubicin- (DNR, 1μM 24hr) and doxorubicin- (DOX, 1.5 μM 24hr) induced apoptosis respectively; as compared to empty vector or untransfected U937 cells (P
Des R. Richardson - One of the best experts on this subject based on the ideXlab platform.
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Unexpected anthracycline-mediated alterations in iron-regulatory protein-RNA-binding activity: the iron and copper complexes of anthracyclines decrease RNA-binding activity.
Molecular Pharmacology, 2002Co-Authors: Juliana C. Kwok, Des R. RichardsonAbstract:Anthracyclines are effective antineoplastic agents. However, the interaction of these drugs with iron (Fe) is an important cause of myocardial toxicity, limiting their therapeutic use (J Lab Clin Med 122:245-251, 1993). To overcome this limitation, it is crucial to understand how anthracyclines interact with the Fe metabolism of myocardial and neoplastic cells. Iron-regulatory proteins (IRPs) play vital roles in regulating cellular Fe metabolism via their mRNA-binding activity. We showed that doxorubicin (DOX) and its analogs interfere with tumor and myocardial cell Fe metabolism by affecting the RNA-binding activity of IRPs. Unexpectedly, experiments with the free radical scavengers, catalase, superoxide dismutase, ebselen, and Mn(III) tetrakis (4-benzoic acid) porphyrin complex, suggested that the effects of DOX on IRP-RNA-binding activity were not due to anthracycline-mediated free radical production. In contrast to previous studies, we showed that the DOX metabolite, doxorubicinol, had no effect on IRP-RNA-binding activity. Rather, the anthracycline-Fe and -copper (Cu) complexes decreased IRP-RNA-binding activity, indicating that formation of anthracycline-metal complexes may affect cellular Fe metabolism. In addition, anthracyclines prevented the response of IRPs to the depletion of intracellular Fe by chelators. This information may be useful in designing novel therapeutic strategies against tumor cells by combining chelators and anthracyclines. Interestingly, the effect of DOX on primary cultures of cardiomyocytes was similar to that observed using neoplastic cells, and particularly notable was the decrease in IRP2-RNA-binding activity. Our results add significant new information regarding the effects of anthracyclines on Fe metabolism that may lead to the design of more effective treatments.
Leontien C. M. Kremer - One of the best experts on this subject based on the ideXlab platform.
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The Cochrane Library - Treatment including anthracyclines versus treatment not including anthracyclines for childhood cancer
The Cochrane database of systematic reviews, 2009Co-Authors: Elvira C. Van Dalen, Martine F. Raphael, Huib N. Caron, Leontien C. M. KremerAbstract:Background One of the most important adverse effects of anthracyclines is cardiotoxicity. A well-informed decision on the use of anthracyclines in the treatment of childhood cancers should be based on evidence regarding both antitumour efficacy and cardiotoxicity. This review is the second update of a previously published Cochrane review. Objectives To compare antitumour efficacy (survival and tumour response) and cardiotoxicity of treatment including or not including anthracyclines in children with childhood cancer. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 6), MEDLINE (1966 to July 2013) and EMBASE (1980 to July 2013). In addition, we searched reference lists of relevant articles and conference proceedings, the International Society for Paediatric Oncology (SIOP) (from 2002 to 2012) and American Society of Clinical Oncology (ASCO) (from 2002 to 2013). We have searched for ongoing trials in the ISRCTN register and the National Institute of Health register (both screened August 2013) (http://www.controlled-trials.com). Selection criteria Randomised controlled trials (RCTs) comparing treatment of any type of childhood cancer with and without anthracyclines and reporting outcomes concerning antitumour efficacy or cardiotoxicity. Data collection and analysis Two review authors independently performed the study selection, risk of bias assessment and data extraction. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. Main results We identified RCTs for seven types of tumour, acute lymphoblastic leukaemia (ALL) (three trials; 912 children), Wilms' tumour (one trial; 316 children), rhabdomyosarcoma and undifferentiated sarcoma (one trial; 413 children), Ewing's sarcoma (one trial; 94 children), non-Hodgkin lymphoma (one trial; 284 children), hepatoblastoma (one trial; 255 children) and acute myeloid leukaemia (AML) (one trial; 394 children). All studies had methodological limitations. For ALL no evidence of a significant difference in antitumour efficacy was identified in the meta-analyses, but in most individual studies there was a suggestion of better antitumour efficacy in patients treated with anthracyclines. For both Wilms' tumour and Ewing's sarcoma a significant difference in event-free and overall survival in favour of treatment with anthracyclines was identified, although for Wilms' tumour the significant difference in overall survival disappeared with long-term follow-up. For rhabdomyosarcoma and undifferentiated sarcoma, non-Hodgkin lymphoma and hepatoblastoma no difference in antitumour efficacy between the treatment groups was identified. The same was true for AML, with the exception of overall survival in a post hoc analysis in a subgroup of patients with relapsed core binding factor (CBF)-AML in which patients treated with anthracyclines did better. Clinical cardiotoxicity was evaluated in four RCTs; no significant difference between the treatment groups was identified, but in all individual studies there was a suggestion of a lower rate of clinical cardiotoxicity in patients who did not receive anthracyclines. None of the studies evaluated asymptomatic cardiac dysfunction. No RCTs were identified for other childhood cancers. Authors' conclusions At the moment no evidence from RCTs is available which underscores the use of anthracyclines in ALL. However, 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For Wilms' tumour, rhabdomyosarcoma and undifferentiated sarcoma, Ewing's sarcoma, non-Hodgkin lymphoma, hepatoblastoma and AML only one RCT was available for each type and, therefore, no definitive conclusions can be made about the antitumour efficacy of treatment with or without anthracyclines in these tumours. For other childhood cancers no RCTs were identified and therefore no conclusions can be made about the antitumour efficacy of treatment with or without anthracyclines in these tumours.
Tiziano Barbui - One of the best experts on this subject based on the ideXlab platform.
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The use of anthracyclines in adult acute lymphoblastic leukemia.
Haematologica, 1995Co-Authors: Renato Bassan, T. Lerede, Alessandro Rambaldi, Maurizio Buelli, Piera Viero, Tiziano BarbuiAbstract:A critical review of the role of anthracyclines in the management of adult patients with acute lymphoblastic leukemia was performed to define current indications for their use. Major pertinent clinical series were reviewed with reference to anthracycline type, cumulative dosage and dose intensity, and administration schedule during both induction therapy and postremission consolidation, comparing results, whenever possible, with non-anthracycline treatment groups. A subgroup analysis was performed to evidentiate disease subtypes likely associated with a favorable outcome to anthracycline treatment. The results indicated that anthracyclines may still play a primary role in this setting. In particular, anthracyclines should be used at full therapeutic doses, especially during induction and early consolidation; idarubicin could be a better choice than daunorubicin or adriamycin; finally, an early brief intensive treatment with anthracyclines may provide an excellent probability of long-term disease-free survival in CD10+ t(9;22)-negative B-precursor adult ALL, obviating the need for prolonged maintenance or late reinduction therapy.
Eleni D. Lagadinou - One of the best experts on this subject based on the ideXlab platform.
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c-Jun N-terminal kinase activation failure is a new mechanism of anthracycline resistance in acute myeloid leukemia.
Leukemia, 2008Co-Authors: Eleni D. Lagadinou, Panagiotis G. Ziros, Olga Tsopra, Kostas Dimas, Panagiotis Pantazis, Alexandros Spyridonidis, D Kokkinou, Eleni Thanopoulou, M. Karakantza, Nicholas C. ZoumbosAbstract:Chemotherapy resistance is a major challenge in acute myeloid leukemia (AML). Besides the P-glycoprotein efflux, additional cellular factors may contribute to drug resistance in AML. c-Jun N-terminal kinase (JNK) is activated after exposure of cells to chemotherapeutics. We asked whether chemoresistance in AML is attributed to intrinsic failure of the AML blasts to activate JNK. In vitro treatment of U937 AML cell line with anthracyclines induced a rapid and robust JNK phosphorylation and apoptosis. In contrast, the anthracyline-resistant derivative cell lines U937R and URD40 showed no JNK activation after exposure to anthracyclines, also at doses that resulted in high accumulation of the drug within the cells. RNA interference-based depletion of JNK1 in drug-sensitive U937 cells made them chemoresistant, whereas selective restoration of the inactive JNK pathway in the resistant U937R cells sensitized them to anthracyclines. Short-term in vitro exposure of primary AML cells (n=29) to daunorubicin showed a strong correlation between the in vitro pharmacodymanic changes of phospho-JNK levels and the response of patients to standard induction chemotherapy (P=0.012). We conclude that JNK activation failure confers another mechanism of anthracycline resistance in AML. Elucidating the ultimate mechanisms leading to JNK suppression in chemoresistant AML may be of major therapeutic value.
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c-Jun N-Terminal Kinase (JNK) Activation Failure Confers a New Mechanism of Anthracycline Resistance in Acute Myeloid Leukemia (AML).
Blood, 2007Co-Authors: Eleni D. Lagadinou, Panagiotis G. Ziros, Olga Tsopra, Kostas Dimas, Panagiotis Pantazis, Alexandros Spyridonidis, Nicholas C. ZoumbosAbstract:Chemotherapy resistance remains a major challenge in the treatment of acute myeloid leukemia (AML). Besides the P-glycoprotein efflux of chemotherapeutics, additional cellular factors may contribute to drug resistance in AML. c- Jun N-terminal Kinase (JNK) is a protein kinase activated after exposure of cells to chemotherapeutic agents. Recently, studies in solid tumours have associated chemoresistance with failure of cancer cells to activate JNK. We asked whether drug resistance in AML is also attributed to intrinsic failure of the AML blasts to activate JNK. In vitro treatment of U937 AML cell line with anthracyclines induced a rapid and robust JNK phosphorylation and apoptosis. In contrast, the anthracyline-resistant derivative U937R cells showed no JNK activation after exposure to anthracyclines, also at doses that resulted in high accumulation of the drug within the cells. Inhibition of JNK in drug-sensitive U937 cells made them resistant to anthracyclines. First, JNK1-siRNA transfected U937 cells exhibited a 50.4% and 61.3% reduced daunorubicin- (DNR, 1μM 24hr) and doxorubicin- (DOX, 1.5 μM 24hr) induced apoptosis respectively; as compared to empty vector or untransfected U937 cells (P