Posted by rob on February 18, 2010 under Uncategorized | 
Arsenic Trioxide-Dependent Activation of TAO2 and TAK1.
Mol Pharmacol. 2010 Feb 16;
Authors: McNeer JL, Goussetis DJ, Sassano A, Dolniak B, Kroczynska B, Glaser H, Altman JK, Platanias LC
Arsenic trioxide (As(2)O(3)) has potent antileukemic properties in vitro and in vivo, but the mechanisms by which it generates its effects on target leukemic cells are not well understood. Understanding cellular mechanisms and pathways that are activated in leukemic cells to control generation of As(2)O(3) responses should have important implications in the development of novel approaches using As(2)O(3) for the treatment of leukemias. In this study, we used immunoblotting and immune complex kinase assays to provide evidence that the kinases TAO2 and TAK1 are rapidly activated in response to treatment of acute leukemia cells with As(2)O(3). Such activation occurs after generation of reactive oxygen species and regulates downstream engagement of the p38 Map kinase. Our studies demonstrate that siRNA-mediated knockdown of TAO2 or TAK1 or pharmacological inhibition of TAK1 enhances the suppressive effects of As(2)O(3) on KT-1-derived leukemic progenitor colony formation and on primary leukemic progenitors from patients with acute myelogenous leukemia. These results indicate key negative-feedback regulatory roles for these kinases in the generation of the antileukemic effects of As(2)O(3). Thus, molecular or pharmacological targeting of these kinases may provide a novel approach to enhance the generation of arsenic-dependent antileukemic responses.
PMID: 20159944 [PubMed - as supplied by publisher]
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Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors.
Nature. 2010 Jan 28;463(7280):501-6
Authors: Zhang J, Adrián FJ, Jahnke W, Cowan-Jacob SW, Li AG, Iacob RE, Sim T, Powers J, Dierks C, Sun F, Guo GR, Ding Q, Okram B, Choi Y, Wojciechowski A, Deng X, Liu G, Fendrich G, Strauss A, Vajpai N, Grzesiek S, Tuntland T, Liu Y, Bursulaya B, Azam M, Manley PW, Engen JR, Daley GQ, Warmuth M, Gray NS
In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr-Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.
PMID: 20072125 [PubMed - indexed for MEDLINE]
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Allogeneic stem cell transplantation for pediatric and adolescent patients with CML: results from the prospective trial CML-paed I.
Klin Padiatr. 2009 Nov-Dec;221(6):351-7
Authors: Suttorp M, Claviez A, Bader P, Peters C, Gadner H, Ebell W, Dilloo D, Kremens B, Kabisch H, Führer M, Zintl F, Göbel U, Klingebiel T
PURPOSE: Stem cell transplantation (SCT) can definitely cure chronic myeloid leukemia (CML), a rare disease in childhood. We prospectively evaluated the results of early SCT in pediatric CML after standardized pretreatment with hydroxyurea+/-interferon. PATIENTS AND METHODS: Between 1995 and 2004, 200 children (median age: 12.4 years) were enrolled and stratified: given the availability of an HLA-matched related donor (MRD), SCT was scheduled within 6 months and otherwise from an unrelated donor (UD) within 12 months following diagnosis. RESULTS: 176 patients underwent SCT; from MRD within median 4 months and from UD within median 11 months after diagnosis. At SCT, 158 patients were in chronic phase (CP1 or CP2), 9 patients were in accelerated phase and 9 patients were in blast crisis (BC). The conditioning regimen – total body irradiation or busulfan – exerted no different impact on overall survival (OS). Probability of OS at 5 years was 87+/-11% if grafted from a sibling (n=41), 52+/-9% from matched UD (MUD, n=71), and 45+/-16% from mismatched donors (MMD, n=55), respectively. A trend for better OS in CP1 was observed if SCT was performed within 6 months (n=49; 74+/-9%), compared to 7-12 months (n=52; 62+/-15%), and >12 months (n=43; 62+/-17%) after diagnosis, respectively (p=0.157). Probability of relapse at 5 years was 20+/-12%. Transplant-related mortality and graft-versus-host disease mainly contributed to the inferior outcome in UD and HLA-mismatched SCT. CONCLUSION: These data from the first prospective trial on CML restricted to children and adolescents might be considered for decision making when balancing the risks of SCT against the increasing use of imatinib as upfront treatment for CML.
PMID: 19890786 [PubMed - indexed for MEDLINE]
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MicroRNA expression profiling in Imatinib-resistant Chronic Myeloid Leukemia patients without clinically significant ABL1-mutations.
Mol Cancer. 2009;8:69
Authors: San José-Enériz E, Román-Gómez J, Jiménez-Velasco A, Garate L, Martin V, Cordeu L, Vilas-Zornoza A, Rodríguez-Otero P, Calasanz MJ, Prósper F, Agirre X
The development of Imatinib Mesylate (IM), the first specific inhibitor of BCR-ABL1, has had a major impact in patients with Chronic Myeloid Leukemia (CML), establishing IM as the standard therapy for CML. Despite the clinical success obtained with the use of IM, primary resistance to IM and molecular evidence of persistent disease has been observed in 20-25% of IM treated patients. The existence of second generation TK inhibitors, which are effective in patients with IM resistance, makes identification of predictors of resistance to IM an important goal in CML. In this study, we have identified a group of 19 miRNAs that may predict clinical resistance to IM in patients with newly diagnosed CML.
PMID: 19723306 [PubMed - indexed for MEDLINE]
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Posted by rob on February 16, 2010 under Uncategorized |
Arsenic trioxide (ATO), an ancient traditional Chinese medicine, has been successfully used as a therapeutic agent for leukemia. Drug resistance and toxicity are major concerns with the treatment. MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that might modulate cellular sensitivity to anticancer drugs. miRNA-21 (miR-21) is one of the most prominent miRNAs involved in various aspects of human cancers. However, miR-21 has been rarely characterized in chronic myelogenous leukemia (CML). Here, we used a specific anti-miR-21 oligonucleotide (AMO-miR-21) to sensitize K562 cells to ATO by degradation of miR-21. The results showed that both AMO-miR-21 and ATO caused growth inhibition, apoptosis, and G1-phase arrest in K562 cells. Meanwhile, AMO-miR-21 significantly promoted ATO…
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This report includes a review of the characteristics of 15 reported cases with co-occurrence of CML and Bcr-Abl-negative CMPDs, including ours. Although rare, care needs to be taken since, despite the often similar clinical features of the two diseases, they require completely different treatments.
PMID: 20146031 [PubMed - as supplied by publisher] (Source: International Journal of Hematology)
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V{gamma}9V{delta}2 T Lymphocytes Efficiently Recognize and Kill Zoledronate-Sensitized, Imatinib-Sensitive, and Imatinib-Resistant Chronic Myelogenous Leukemia Cells.
J Immunol. 2010 Feb 12;
Authors: D’Asaro M, La Mendola C, Di Liberto D, Orlando V, Todaro M, Spina M, Guggino G, Meraviglia S, Caccamo N, Messina A, Salerno A, Di Raimondo F, Vigneri P, Stassi G, Fourniè JJ, Dieli F
Imatinib mesylate (imatinib), a competitive inhibitor of the BCR-ABL tyrosine kinase, is highly effective against chronic myelogenous leukemia (CML) cells. However, because 20-30% of patients affected by CML display either primary or secondary resistance to imatinib, intentional activation of Vgamma9Vdelta2 T cells by phosphoantigens or by agents that cause their accumulation within cells, such as zoledronate, may represent a promising strategy for the design of a novel and highly innovative immunotherapy capable to overcome imatinib resistance. In this study, we show that Vgamma9Vdelta2 T lymphocytes recognize, trogocytose, and efficiently kill imatinib-sensitive and -resistant CML cell lines pretreated with zoledronate. Vgamma9Vdelta2 T cell cytotoxicity was largely dependent on the granule exocytosis- and partly on TRAIL-mediated pathways, was TCR-mediated, and required isoprenoid biosynthesis by zoledronate-treated CML cells. Importantly, Vgamma9Vdelta2 T cells from patients with CML can be induced by zoledronate to develop antitumor activity against autologous and allogeneic zoledronate-treated leukemia cells, both in vitro and when transferred into immunodeficient mice in vivo. We conclude that intentional activation of Vgamma9Vdelta2 T cells by zoledronate may substantially increase their antileukemia activities and represent a novel strategy for CML immunotherapy.
PMID: 20154204 [PubMed - as supplied by publisher]
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Electrochemical biosensor based on nanogold-modified poly-eriochrome black T film for BCR/ABL fusion gene assay by using hairpin LNA probe.
Talanta. 2010 Mar 15;80(5):2113-2119
Authors: Lin L, Chen J, Lin Q, Chen W, Chen J, Yao H, Liu A, Lin X, Chen Y
A novel electrochemical biosensor is described for detection of breakpoint cluster region gene and a cellular abl (BCR/ABL) fusion gene in chronic myelogenous leukemia (CML) by using thiolated-hairpin locked nucleic acids (LNA) as the capture probe. The hairpin LNA probe was immobilized on the nanogold (NG)/poly-eriochrome black T (EBT) film-modified glassy carbon electrode (GCE). The immobilized LNA probe could selectively hybridize with its target DNA on LNA/NG/EBT/GCE surface. The immobilization and hybridization of the LNA probe were characterized with cyclic voltammetry and electrochemical impedance spectroscopy. The hybridization of the immobilized LNA probe with the target DNA was detected by differential pulse voltammetry with the electroactive methylene blue as an indicator. The results indicated this new method has excellent specificity for single-base mismatch and complementary after hybridization, and a high sensitivity. This novel electrochemical biosensor has been used for assay of PCR real sample with satisfactory result.
PMID: 20152460 [PubMed - as supplied by publisher]
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Posted by rob on February 15, 2010 under Uncategorized |
Design, synthesis, and biological evaluation of novel water-soluble triptolide derivatives: Antineoplastic activity against imatinib-resistant CML cells bearing T315I mutant Bcr-Abl.
Bioorg Med Chem. 2010 Jan 25;
Authors: Xu F, Shi X, Li S, Cui J, Lu Z, Jin Y, Lin Y, Pang J, Pan J
Imatinib (STI571) is the frontline targeted-therapeutic agent for patients with chronic myelogenous leukemia (CML). However, resistance to imatinib due to point mutations in Bcr-Abl kinase domain is an emerging problem. We recently reported that triptolide (compound 1) could effectively kill CML cells including those harboring T315I mutant Bcr-Abl. In the present study, we designed a series of C-14 triptolide derivatives with C-14-hydroxyl substituted by different amine esters (3-18): 3-6 and 13 (by aliphatic chain amine esters); 7-9, 11, 12 and 15-18 (by alicyclic amine esters with different size), and 10 and 14 (by aralkylamine esters).The compounds were examined for their antineoplastic activity against CML cells (including KBM5-T315I cells) in terms of proliferation inhibition, apoptosis and signal transduction. Nude mouse xenograft model was also used to evaluate the in vivo activity. Compounds 2-9, 11-14, 17 and 18 exhibited a potent inhibitory activity against KBM5 and KBM5-T315I cells. This series of derivatives down-regulated Bcr-Abl mRNA. Compounds 4, 5, 8 and 9 were further examined for their impact on signaling and apoptosis with immunoblotting. Compound 5 was chosen for evaluation in a nude mouse xenograft model. The stereo-hindrance of C-14 group appeared to be responsible for the antitumor effect. The computational small molecule-protein docking analysis illustrated the possible interaction between compound 9 and RNA polymerase II. Our results suggest that this series of derivatives may be promising agents to overcome imatinib-resistance caused by the Bcr-Abl-T315I mutation.
PMID: 20149665 [PubMed - as supplied by publisher]
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Anti-miR-21 oligonucleotide sensitizes leukemic K562 cells to arsenic trioxide by inducing apoptosis.
Cancer Sci. 2010 Jan 7;
Authors: Li Y, Zhu X, Gu J, Dong D, Yao J, Lin C, Huang K, Fei J
Arsenic trioxide (ATO), an ancient traditional Chinese medicine, has been successfully used as a therapeutic agent for leukemia. Drug resistance and toxicity are major concerns with the treatment. MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that might modulate cellular sensitivity to anticancer drugs. miRNA-21 (miR-21) is one of the most prominent miRNAs involved in various aspects of human cancers. However, miR-21 has been rarely characterized in chronic myelogenous leukemia (CML). Here, we used a specific anti-miR-21 oligonucleotide (AMO-miR-21) to sensitize K562 cells to ATO by degradation of miR-21. The results showed that both AMO-miR-21 and ATO caused growth inhibition, apoptosis, and G1-phase arrest in K562 cells. Meanwhile, AMO-miR-21 significantly promoted ATO-mediated growth inhibition and apotosis without affecting the G1 phase. Apoptotic cells were confirmed morphologically with Giemsa’s staining. Furthermore, dual-luciferase reporter vector, containing two tandem miR-21 binding sites from PDCD4 3′UTR, validated that PDCD4 was directly regulated by miR-21. Therefore, AMO-miR-21 sensitized leukemic K562 cells to ATO by inducing apoptosis partially due to its up-regulation of PDCD4 protein level. The combination of ATO and AMO-miR-21 present therapeutic potential for CML. (Cancer Sci 2010).
PMID: 20148895 [PubMed - as supplied by publisher]
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Posted by rob on February 10, 2010 under Uncategorized |
miRNA-21 regulates arsenic-induced anti-leukemia activity in myelogenous cell lines.
Med Oncol. 2010 Feb 9;
Authors: Gu J, Zhu X, Li Y, Dong D, Yao J, Lin C, Huang K, Hu H, Fei J
MicroRNAs (miRNAs) are endogenous small noncoding RNA molecules involved in modulation of cellular sensitivity to anti-cancer drugs. miRNA-21 (miR-21), one of the most prominent miRNAs in the genesis and progression of many human cancers, has been rarely characterized in myelogenous leukemia. Arsenic trioxide (ATO) was successfully used in the treatment of acute promyelocytic leukemia (APL) etc. However, cytotoxicity or insensitivity is a major concern in the successful treatment of leukemia. Here, we used a specific precursor miRNA-21 (pre-miR-21) or anti-miRNA-21 oligonucleotide (AMO-miR-21) to study sensitivity of HL60 and K562 cells to ATO. Cell viability and cell cycle were evaluated by MTT assay and PI assay using flow cytometry, respectively. Levels of miR-21 and its target PDCD4 were quantified by real-time PCR and/or western blot. AMO-miR-21 or ATO alone led to growth inhibition, apoptosis and G1 phase arrest of cell cycle. Apoptotic cells were confirmed morphologically with Hoechst staining. Moreover, there was somewhat synergistic effect of AMO-miR-21 and ATO in growth inhibition and apoptosis promotion. Meanwhile, enforced pre-miR-21 expression increased resistance to ATO, nevertheless not affecting cell growth alone. Dual-luciferase reporter vector containing two tandem PDCD4 3′ UTR validated that PDCD4 was directly up-regulated by miR-21. Therefore, miRNA-21 by targeting PDCD4 may play a functional role in modulating ATO-induced cell death, and strategy using AMO-miR-21 and its combination with ATO may be useful as a myelogenous leukemia therapy.
PMID: 20143188 [PubMed - as supplied by publisher]
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Sustained Molecular Response With Interferon Alfa Maintenance After Induction Therapy With Imatinib Plus Interferon Alfa in Patients With Chronic Myeloid Leukemia.
J Clin Oncol. 2010 Feb 8;
Authors: Burchert A, Müller MC, Kostrewa P, Erben P, Bostel T, Liebler S, Hehlmann R, Neubauer A, Hochhaus A
PURPOSE: Imatinib induces sustained remissions in patients with chronic myelogenous leukemia (CML), but fails to eradicate CML stem cells. This is of major concern regarding the issues of cure, long-term imatinib tolerability, and imatinib resistance. We therefore asked whether interferon alfa-2a (IFN) alone could maintain molecular remissions achieved by a prior combination therapy with imatinib and IFN. PATIENTS AND METHODS: Imatinib therapy was stopped in 20 patients who had concomitantly been pretreated with imatinib and IFN for a median of 2.4 years (range, 0.2 to 4.8 years) and 2.5 years (range, 0.2 to 4.9 years), respectively. After imatinib discontinuation, remission status was monitored monthly by quantitative analysis of the peripheral-blood BCR-ABL mRNA levels using real-time polymerase chain reaction. Proteinase-3 expression and proteinase-3-specific cytotoxic T cells (CTLs) were longitudinally measured to assess putative markers of IFN response. RESULTS: With a median time of 2.4 years after imatinib withdrawal (range, 0.5 to 4.0 years), 15 (75%) of 20 patients remained in remission. The number of patients in complete molecular remission increased under IFN from two patients at baseline to five patients after 2 years. Relapses occurred in five patients within 0.4 years (range, 0.2 to 0.8 years), but patients underwent rescue treatment with imatinib, re-establishing molecular remission. IFN therapy was associated with an increase in the expression of leukemia-associated antigen proteinase 3 and induction of proteinase-3-specific CTLs. CONCLUSION: Treatment with IFN enables discontinuation of imatinib in most patients after prior imatinib/IFN combination therapy and may result in improved molecular response. Induction of a proteinase-3-specific CTL response by IFN may contribute to this effect.
PMID: 20142590 [PubMed - as supplied by publisher]
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Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations.
J Exp Med. 2010 Feb 8;
Authors: Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG, Sasaki M, Jin S, Schenkein DP, Su SM, Dang L, Fantin VR, Mak TW
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), are present in most gliomas and secondary glioblastomas, but are rare in other neoplasms. IDH1/2 mutations are heterozygous, and affect a single arginine residue. Recently, IDH1 mutations were identified in 8% of acute myelogenous leukemia (AML) patients. A glioma study revealed that IDH1 mutations cause a gain-of-function, resulting in the production and accumulation of 2-hydroxyglutarate (2-HG). Genotyping of 145 AML biopsies identified 11 IDH1 R132 mutant samples. Liquid chromatography-mass spectrometry metabolite screening revealed increased 2-HG levels in IDH1 R132 mutant cells and sera, and uncovered two IDH2 R172K mutations. IDH1/2 mutations were associated with normal karyotypes. Recombinant IDH1 R132C and IDH2 R172K proteins catalyze the novel nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of alpha-ketoglutarate (alpha-KG) to 2-HG. The IDH1 R132C mutation commonly found in AML reduces the affinity for isocitrate, and increases the affinity for NADPH and alpha-KG. This prevents the oxidative decarboxylation of isocitrate to alpha-KG, and facilitates the conversion of alpha-KG to 2-HG. IDH1/2 mutations confer an enzymatic gain of function that dramatically increases 2-HG in AML. This provides an explanation for the heterozygous acquisition of these mutations during tumorigenesis. 2-HG is a tractable metabolic biomarker of mutant IDH1/2 enzyme activity.
PMID: 20142433 [PubMed - as supplied by publisher]
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Antisense oligonucleotide against miR-21 inhibits migration and induces apoptosis in leukemic K562 cells.
Leuk Lymphoma. 2010 Feb 8;
Authors: Hu H, Li Y, Gu J, Zhu X, Dong D, Yao J, Lin C, Fei J
MicroRNAs (miRNAs) are small non-coding RNA molecules that are widely involved in cancer-related processes. The microRNA-21 (miR-21) has been identified as the only miRNA overexpressed in a variety of cancers, including leukemia. However, the function of miR-21 is yet unknown in chronic myelogenous leukemia (CML). Antisense oligonucleotides (ASOs), as inhibitors of miRNAs, have already been applied to therapeutic development and functional identification in miRNA research. In this study, we found that the antisense inhibition of miR-21 in K562 cells suppressed cell migration, promoted cell apoptosis, and inhibited cell growth, and up-regulated the expression of the tumor suppressor gene PDCD4. Meanwhile, pre-miRNA-21 increased migration and decreased cell apoptosis without affecting proliferation. We also validated that PDCD4 is a functional target of miR-21 in K562 cells. These effects of miR-21 might be partially due to its regulation of PDCD4. Our data suggest that miR-21 may play an oncogenic role in the cellular processes of CML, and antisense inhibition of miR-21 may therefore be useful as CML therapy.
PMID: 20141427 [PubMed - as supplied by publisher]
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Substance Use and Survival after Treatment for Chronic Myelogenous Leukemia (CML) or Myelodysplastic Syndrome (MDS).
Am J Drug Alcohol Abuse. 2010 Jan;36(1):1-6
Authors: Chang G, Meadows ME, Jones JA, Antin JH, Orav EJ
Background: Patients’ substance use problems are a particularly understudied aspect of psychosocial variables in cancer treatment. Objectives: The specific hypothesis tested was that lifetime substance use disorders increased the risk of adverse outcome, in the context of other psychosocial and clinical characteristics demonstrated in other studies to have an impact on treatment outcome. Method: Prospective cohort study of 106 adults with chronic myelogenous leukemia or primary myelodysplastic syndrome. None satisfied criteria for current substance abuse or dependence, but the lifetime rates of substance use disorders in this sample were 28% for alcohol, 12% for cannabis, and 9% for cocaine. Results: Participants received treatment as directed by their physicians, and were followed until death or the end of the study (median 1.5 years). Twenty-eight died. Multivariate survival analysis identified three predictors of outcome: lifetime cocaine use, associated with a six-fold increased risk of death (p = .04), and two protective variables, baseline hemoglobin (p = .002) and estimated intelligence quotient (IQ) (p = .04). Conclusion: The results of this study highlight the potential significance of substance use disorders, and lifetime cocaine diagnoses in particular, on treatment outcome for people with chronic myelogenous leukemia or myelodysplastic syndrome. Whereas neither lifetime alcohol nor cannabis use were associated with survival on either the univariate or multivariate models of survival, lifetime cocaine diagnoses were associated with significant six-fold increased risk of death (p = .04).
PMID: 20141389 [PubMed - in process]
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Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter?
Blood. 2009 Dec 24;114(27):5426-35
Authors: Branford S, Melo JV, Hughes TP
Preclinical studies of BCR-ABL mutation sensitivity to nilotinib or dasatinib suggested that the majority would be sensitive. Correspondingly, the initial clinical trials demonstrated similar response rates for CML patients after imatinib failure, irrespective of the mutation status. However, on closer examination, clinical evidence now indicates that some mutations are less sensitive to nilotinib (Y253H, E255K/V, and F359V/C) or dasatinib (F317L and V299L). T315I is insensitive to both. Novel mutations (F317I/V/C and T315A) are less sensitive/insensitive to dasatinib. We refer to these collectively as second-generation inhibitor (SGI) clinically relevant mutations. By in vitro analysis, other mutations confer a degree of insensitivity; however, clinical evidence is currently insufficient to define them as SGI clinically relevant. Here we examine the mutations that are clearly SGI clinically relevant, those with minimal impact on response, and those for which more data are needed. In our series of patients with mutations at imatinib cessation and/or at nilotinib or dasatinib commencement, 43% had SGI clinically relevant mutations, including 14% with T315I. The frequency of SGI clinically relevant mutations was dependent on the disease phase at imatinib failure. The clinical data suggest that a mutation will often be detectable after imatinib failure for which there is compelling clinical evidence that one SGI should be preferred.
PMID: 19880502 [PubMed - indexed for MEDLINE]
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Posted by rob on February 7, 2010 under Uncategorized |
Acquired resistance through genetic mutations is a common phenomenon in several cancer therapies using molecularly targeted drugs, best exemplified by the BCR-ABL inhibitor imatinib in treating chronic myelogenous leukemia (CML). Overcoming acquired resistance is a daunting therapeutic challenge, and little is known about how these mutations evolve. To facilitate understanding the resistance mechanisms, we developed a novel culture model for CML acquired resistance in which the CML cell line KCL-22, following initial response to imatinib, develops resistant T315I BCR-ABL mutation. We demonstrate that the emergence of BCR-ABL mutations do not require pre-existing BCR-ABL mutations derived from the original patient as the subclones of KCL-22 cells can form various BCR-ABL mutations upon imat…
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Drug costs and utilization after implementation of a posaconazole prophylaxis protocol in adults with acute myelogenous leukemia.
Am J Health Syst Pharm. 2010 Feb 15;67(4):295-9
Authors: Nemerovski CW, Mackler ER, Depestel DD, Collins CD, Welch KS, Stevenson JG
Purpose Drug costs and utilization after implementation of a posaconazole prophylaxis protocol in adults with acute myelogenous leukemia (AML) were studied. Methods Adult patients who initiated induction or reinduction chemotherapy for the treatment of AML between December 1, 2006, and March 31, 2008, at a tertiary care hospital were included in this retrospective cohort study. Patients were divided into two groups: preprotocol (treated before June 1, 2007) and postprotocol (treated on or after June 1, 2007). Medical charts, including pharmacy and laboratory data, were reviewed for all patients. Outcomes measured included antifungal and antibacterial drug costs and utilization and total pharmacy costs. Results A total of 66 patients were evaluated (33 in each group). Baseline characteristics, except patient age, were similar between groups. Each group incurred similar costs and utilized resources for similar periods of time as evidenced by similar lengths of stay, duration of neutropenia, and mortality. Antibacterial costs, total pharmacy costs, and other utilization outcomes were also similar between the two groups. Alterations to antifungal management strategy occurred more often in the postprotocol group (33% versus 58%, p = 0.048). Conclusion Implementation of a posaconazole protocol did not significantly alter antifungal or antibacterial drug costs or utilization or total pharmacy costs. Prophylactic posaconazole was frequently changed to alternative antifungal therapy due to an adverse drug event, perceived lack of efficacy, avoidance of a drug interaction, or inability to tolerate oral intake.
PMID: 20133535 [PubMed - in process]
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Whither the bone marrow transplant?
Hematology. 2010 Feb;15(1):1-3
Authors: Ruiz-Argüelles GJ
Bone marrow transplantation (BMT) has become an accepted and important medical intervention which has become a routine part of medical practice. Its utility has, however, been questioned recently in a number of diseases in which its role has been clearly established on the basis that there are better non-transplant therapeutic options. The suspicion that these moves to eradicate BMT as an option may not stem from purely scientific reasons has prompted the preparation of these personal reflections. I will focus this discussion only on two diseases in which BMT has been shown to be useful: chronic myelogenous leukemia (CML) and multiple myeloma (MM).
PMID: 20132655 [PubMed - in process]
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Effect of magnetic nanoparticles of Fe3O4 and 5-bromotetrandrine on reversal of multidrug resistance in K562/A02 leukemic cells.
Int J Nanomedicine. 2009;4:209-16
Authors: Cheng J, Wu W, Chen BA, Gao F, Xu W, Gao C, Ding J, Sun Y, Song H, Bao W, Sun X, Xu C, Chen W, Chen N, Liu L, Xia G, Li X, Wang X
This study aims to evaluate the multidrug resistance (MDR) reversal activity by magnetic nanoparticles of Fe3O4 (MNPs-Fe3O4) and 5-bromotetrandrine (BrTet) MDR cell line K562/A02 solitarily or symphysially. The proliferation of K562 and K562/A02 cells and the cytotoxicity on peripheral blood mononuclear cells (PMBCs) were evaluated by MTT assay. Cellular accumulation of daunorubicin (DNR) was analyzed by flow cytometry. Real-time polymerase chain reaction and Western blotting analyses were performed to examine the mRNA and protein levels of mdr1, respectively. The results showed that the combination of MNPs-Fe3O4 and BrTet with effective concentrations significantly increased cytotoxicity against MDR cell line K562/A02. Both BrTet and MNPs-Fe3O4 increased the intracellular DNR accumulation in the K562/A02 cell line, and downregulated the level of mdr1 gene and expression of P-glycoprotein. Furthermore, the combination did not have significant cytotoxicity in PMBCs. We propose that MNPs-Fe3O4 conjugated with DNR and BrTet probably have synergetic effects on MDR reversal.
PMID: 19918367 [PubMed - indexed for MEDLINE]
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