Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: when is this a safe option to consider?
Hematology Am Soc Hematol Educ Program. 2013;2013:184-8
Authors: Sweet K, Oehler V
Mrs G is a 54-year-old woman with a diagnosis of chronic-phase chronic myeloid leukemia dating back 8 years. She had a low-risk Sokal score at diagnosis and was started on imatinib mesylate at 400 mg orally daily within one month of her diagnosis. Her 3-month evaluation revealed a molecular response measured by quantitative RT-PCR of 1.2% by the International Scale. Within 6 months of therapy, she achieved a complete cytogenetic response, and by 18 months, her BCR-ABL1 transcript levels were undetectable using a quantitative RT-PCR assay with a sensitivity of ? 4.5 logs. She has maintained this deep level of response for the past 6.5 years. Despite her excellent response to therapy, she continues to complain of fatigue, intermittent nausea, and weight gain. She is asking to discontinue imatinib mesylate and is not interested in second-line therapy. Is this a safe and reasonable option for this patient?
PMID: 24319180 [PubMed - indexed for MEDLINE]
Update on current monitoring recommendations in chronic myeloid leukemia: practical points for clinical practice.
Hematology Am Soc Hematol Educ Program. 2013;2013:176-83
Authors: Oehler VG
Excellent therapeutic options exist for the treatment of chronic-phase chronic myeloid leukemia (CML) patients. Therefore, managing CML patients has become a more common practice for many physicians. Most chronic-phase CML patients achieve durable cytogenetic and molecular responses on first-line tyrosine kinase inhibitor therapy. However, careful monitoring and assessment of adherence are essential for successful outcomes and to identify patients at risk for failing therapy. The European LeukemiaNet and National Comprehensive Cancer Network provide guidance and strategies for monitoring and managing patients treated with TKIs. These recommendations continue to evolve as approved treatment options expand to include second- and third-generation tyrosine kinase inhibitors. How measurements of response are defined and data supporting recent recommended changes to monitoring are reviewed here. These changes include increasing recognition of the importance of early response. The relevance of achieving deep molecular responses will also be addressed.
PMID: 24319179 [PubMed - indexed for MEDLINE]
Which TKI? An embarrassment of riches for chronic myeloid leukemia patients.
Hematology Am Soc Hematol Educ Program. 2013;2013:168-75
Authors: Hughes T, White D
With the approval in many countries of nilotinib and dasatinib for frontline therapy in chronic myeloid leukemia, clinicians now have to make a difficult choice. Because none of the 3 available tyrosine kinase inhibitors (TKIs) have shown a clear survival advantage, they all represent reasonable choices. However, in individual patients, the case may be stronger for a particular TKI. In the younger patient, in whom the prospect of eventually achieving treatment-free remission is likely to be of great importance, dasatinib or nilotinib may be preferred, although their advantage over imatinib in this setting remains to be proven. In patients with a higher risk of transformation (which is currently based on prognostic scoring), the more potent TKIs may be preferred because they appear to be more effective at reducing the risk of transformation to BC. However, imatinib still represents an excellent choice for many chronic myeloid leukemia patients. All of these considerations need to be made in the context of the patient’s comorbidities, which may lead to one or more TKIs being ruled out of contention. Whatever first choice of TKI is made, treatment failure or intolerance must be recognized early because a prompt switch to another TKI likely provides the best chance of achieving optimal response.
PMID: 24319178 [PubMed - indexed for MEDLINE]
Correlations between cytogenetic and molecular monitoring among patients with newly diagnosed chronic myeloid leukemia in chronic phase: post hoc analyses of the Rationale and Insight for Gleevec High-Dose Therapy study.
Arch Pathol Lab Med. 2014 Sep;138(9):1186-92
Authors: Akard LP, Cortes JE, Albitar M, Goldberg SL, Warsi G, Wetzler M, Ericson SG, Radich JP
CONTEXT: Although bone marrow (BM) karyotyping has been the standard in monitoring patients with chronic myeloid leukemia, peripheral blood (PB) monitoring methods may be more convenient.
OBJECTIVE: To conduct post hoc analyses of the Rationale and Insight for Gleevec High-Dose Therapy study to evaluate correlations between results of cytogenetic testing and molecular monitoring from BM and PB during the first 18 months of high-dose imatinib therapy, and between early and late molecular responses.
DESIGN: Newly diagnosed patients with chronic-phase chronic myeloid leukemia received imatinib 400 mg twice daily and were monitored quarterly for up to 18 months. Cytogenetic testing was performed by karyotyping using BM or by fluorescence in situ hybridization using PB. Molecular testing was performed by quantitative reverse transcriptase polymerase chain reaction using BM and PB.
RESULTS: Significant pairwise correlations were found between results obtained by karyotyping, fluorescence in situ hybridization, and quantitative reverse transcriptase polymerase chain reaction using PB or BM (all pairwise correlations >0.8; P < .001). At 12 months, cytogenetic response by karyotyping correlated well with response by fluorescence in situ hybridization. A median 2.579-log reduction in BCR-ABL1 level from a standardized baseline correlated with fluorescence in situ hybridization-negative status. Patients with greater than 2-log reduction in BCR-ABL1 level at 3, 6, and 9 months were more likely to achieve major molecular response at 18 months than those with 2-log reduction or less.
CONCLUSIONS: Our findings support the feasibility of molecular monitoring using PB and suggest that molecular monitoring conducted at a single reliable reference laboratory can adequately track response without invasive BM testing. Our findings are consistent with other work indicating that early response to imatinib predicts favorable long-term outcome.
PMID: 24308645 [PubMed - indexed for MEDLINE]
OCT1 genetic variants are associated with long term outcomes in imatinib treated chronic myeloid leukemia patients.
Eur J Haematol. 2014 Apr;92(4):283-8
Authors: Koren-Michowitz M, Buzaglo Z, Ribakovsky E, Schwarz M, Pessach I, Shimoni A, Beider K, Amariglio N, le Coutre P, Nagler A
OBJECTIVES: One third of CML patients treated with first line imatinib have suboptimal responses or treatment failures with increased risk for disease progression. Imatinib is actively transported into cells by the SLC22A1 transporter (hOCT1) and its genetic variants may affect intracellular drug import. We studied the effect of SLC22A1 genetic variants on long-term outcomes of imatinib treated patients.
METHODS: A total of 167 patients, 94% in chronic phase, were analyzed for rs41267797, rs683369, rs12208357, and rs628031 variants using the Sequenom MassARRAY platform.
RESULTS: Rates of CHR, MCyR, CCyR, and MMolR were not significantly different according to allelic variants. However, patients with AA or GA rs628031 genotypes had a higher incidence of poor response to imatinib compared to the GG genotype (47% compared to 29%, P = 0.06), and a higher rate of KD mutation discovery (8/16 vs. 5/27, P = 0.04), suggesting that secondary resistance was more common in these genotypes. Median EFS was shorter for rs628031 genotype AA/AG compared with the GG genotype (61 months and not reached, respectively, P = 0.05), and 5 yr OS rates were lower for patients with the rs628031 genotypes AA/AG compared with the GG genotype (88% and 97%, respectively, P = 0.03). Patients with AA/GA rs628031 and additional rare genotypes had worse EFS and OS compared to patients with only AA/GA rs628031 (P = 0.02 for EFS and 0.01 for OS). There was no difference in pretreatment SLC22A1 mRNA expression levels in patients with rs628031 genotypes GG/AA or GA.
CONCLUSIONS: Studying SLC22A1 genetic variants prior to TKI initiation could influence treatment decisions.
PMID: 24215657 [PubMed - indexed for MEDLINE]
Fenretinide targets chronic myeloid leukemia stem/progenitor cells by regulation of redox signaling.
Antioxid Redox Signal. 2014 Apr 20;20(12):1866-80
Authors: Du Y, Xia Y, Pan X, Chen Z, Wang A, Wang K, Li J, Zhang J
AIMS: We have recently shown that fenretinide preferentially targets CD34(+) cells of acute myeloid leukemia (AML), and here, we test whether this agent exerts the effect on CD34(+) cells of chronic myeloid leukemia (CML), which are refractory to imatinib.
RESULTS: As tested by colony-forming cell assays using clinical specimens, both number and size of total colonies derived from CD34(+) CML cells were significantly reduced by fenretinide, and by combining fenretinide with imatinib. In particular, colonies derived from erythroid progenitors and more primitive pluripotent/multipotent progenitors were highly sensitive to fenretinide/fenretinide plus imatinib. Accordantly, fenretinide appeared to induce apoptosis in CD34(+) CML cells, particularly with regard to the cells in the subpopulation of CD34(+)CD38(-). Through cell quiescent assays, including Ki-67 negativity test, we added evidence that nonproliferative CD34(+) CML cells were largely eliminated by fenretinide. Transcriptome and molecular data further showed that mechanisms underlying the apoptosis in CD34(+) CML cells were highly complex, involving multiple events of oxidative stress responses.
INNOVATION AND CONCLUSION: As compared with CD34(+) AML cells, the apoptotic effects of fenretinide on CD34(+) CML cells were more prominent whereas less varied among the samples of different patients, and also various stress-responsive events appeared to be more robust in fenretinide-treated CD34(+) CML cells. Thus, the combination of fenretinide with imatinib may represent a more sophisticated strategy for CML treatment, in which imatinib mainly targets leukemic blast cells through the intrinsic pathway of apopotosis, whereas fenretinide primarily targets CML stem/progenitor cells through the oxidative/endoplasmic reticulum stress-mediated pathway.
PMID: 24021153 [PubMed - indexed for MEDLINE]
Proteomic-based identification of Apg-2 as a therapeutic target for chronic myeloid leukemia.
Cell Signal. 2013 Dec;25(12):2604-12
Authors: Li Y, Chen X, Shi M, Wang H, Cao W, Wang X, Li C, Feng W
The oncogenic BCR/ABL tyrosine kinase induces constitutive enhanced “spontaneous” DNA damage and unfaithful repair in Philadelphia chromosome positive leukemia cells. Here, we investigated the changes of protein profile in H2O2-induced DNA damage/repair in BaF3-MIGR1 and BaF3-BCR/ABL cells through a proteomic strategy consisting of two-dimensional gel electrophoresis (2-DE) coupled with MALDI-TOF mass spectrometry. In total, 41 spots were differentially expressed and 13 proteins were identified with further MS analysis. Two essential proteins, Proto-oncogene tyrosine-protein kinase ABL1 (c-ABL) and Heat shock 70kDa protein 4 (Apg-2), were confirmed by Western blot and showed consistent changes with proteomic results. Moreover, functional analysis demonstrated that inhibition of Apg-2 not only decreased cell proliferation, but also induced cell apoptosis in BCR/ABL positive cells (BaF3-BCR/ABL, BaF3-BCR/ABL(T315I)). We also proved that Apg-2 inhibition aggravated H2O2 induced damage in BCR/ABL positive cells, and enhanced the sensitivity of BaF3-BCR/ABL(T315I) to STI571. Taken together, the findings in this work provide us with some clues to a better understanding of the molecular mechanisms underlying BCR/ABL in the DNA damage/repair processes and demonstrated that Apg-2 would be a valid target for anti-leukemia drug development.
PMID: 24012954 [PubMed - indexed for MEDLINE]
Incidence of internal tandem duplications and D835 mutations of FLT3 gene in chronic myeloid leukemia patients from Southern India.
Hematology. 2014 Apr;19(3):129-35
Authors: Annamaneni S, Kagita S, Gorre M, Digumarti RR, Satti V, Battini MR
OBJECTIVE: To screen two important FLT3 mutations (internal tandem duplication (ITD) and D835 point mutations) in chronic myeloid leukemia (CML) patients from Southern India and report their incidence.
METHODS: Screened 350 CML patients and 350 controls for the two FLT3/mutations through polymerase chain reaction and restriction fragment length polymorphism methods.
RESULTS: ITDs were detected in 12 of the 350 CML patients (3.4%) and D835 mutations in only four cases (1.14%), relatively low in frequency as compared to those reported earlier from non-Indian populations. None of the cases showed simultaneous occurence of both ITD and D835 mutations.
DISCUSSION: These FLT3 mutations seem to be very rare in CML, and it is possible that these could be found only in a subset of patients who are in the progressive stage and/or with varied drug response. Prospective studies are needed to confirm the role of FLT3 mutations in CML pathogenesis, which may help devising therapeutic interventions.
PMID: 23796006 [PubMed - indexed for MEDLINE]
Association of MDR1 gene polymorphism (G2677T) with imatinib response in Egyptian chronic myeloid leukemia patients.
Hematology. 2014 Apr;19(3):123-8
Authors: Elghannam DM, Ibrahim L, Ebrahim MA, Azmy E, Hakem H
BACKGROUND: Despite the excellent efficacy results of imatinib treatment in CML patients, resistance to imatinib has emerged as a significant problem. Genetic variations in genes involved in drug transportation might influence the pharmacokinetic and metabolism of imatinib. The genotype of a patient is increasingly recognized in influencing the response to the treatment.
AIM: To investigate the genotype frequencies of single nucleotide polymorphisms (SNPs) G2677T in CML patients undergoing imatinib treatment to determine whether different genotype pattern of these SNPs have any influence in mediating response to imatinib.
METHODS: A total of 96 CML and 90 control samples were analyzed for the human multidrug resistance gene 1 (MDR1) gene polymorphism (G2677T) using polymerase chain reaction-restriction fragment length polymorphism technique.
RESULTS: Genotype distribution revealed a significant lower frequency of TT genotype in CML patients and non-significant difference in the GG, GT genotype frequencies between patients and controls (P = 0.004, 0.138, 0.210, respectively). GG genotype was significantly higher in chronic phase (P = 0.046), while GT genotype was significantly higher in Blastic crisis phase (P = 0.002). There was a significant difference in genotype frequency of G2677T among patients showing response and resistance to imatinib in chronic phase (P = 0.02). TT genotype was associated with complete hematological response (P = 0.01), complete cytogenetic response (P < 0.001), and better molecular response with a significant association (P < 0.001). GT genotype was associated with partial hematological response (P = 0.01) and minor cytogenetic response (P < 0.001). Optimal and suboptimal responses were observed for patients with TT genotype (P = 0.003). Failure of drug response was associated with GT genotype (P = 0.02); however, GG had no association with drug response. Multivariate analysis considered GT genotype as independent risk factor for resistance (P = 0.037), while TT genotype as protective factor against resistance to imatinib (P = 0.008).
CONCLUSION: Determination of MDR1 polymorphisms (G2677T) might be useful in response prediction to therapy with imatinib in patients with CML.
PMID: 23683876 [PubMed - indexed for MEDLINE]
Clinical spectrum and long-term follow-up of 14 cases with G6PC3 mutations from the French severe congenital neutropenia registry.
Orphanet J Rare Dis. 2014 Dec 10;9(1):183
Authors: Desplantes C, Fremond M, Beaupain B, Harousseau J, Buzyn A, Pellier I, Roques G, Morville P, Paillard C, Bruneau J, Pinson L, Jeziorski E, Vannier J, Picard C, Bellanger F, Romero N, de Pontual L, Lapillonne H, Lutz P, Chantelot C, Donadieu J
BackgroundThe purpose of this study was to describe the natural history of severe congenital neutropenia (SCN) in 14 patients with G6PC3 mutations and enrolled in the French SCN registry.MethodsAmong 605 patients included in the French SCN registry, we identified 8 pedigrees that included 14 patients with autosomal recessive G6PC3 mutations.ResultsMedian age at the last visit was 22.4 years. All patients had developed various comordibities, including prominent veins (n¿=¿12), cardiac malformations (n¿=¿12), intellectual disability (n¿=¿7), and myopathic syndrome with recurrent painful cramps (n¿=¿1). Three patients developed Crohn¿s disease, and five had chronic diarrhea with steatorrhea. Neutropenia was profound (<0.5¿×¿109/l) in almost all cases at diagnosis and could marginally fluctuate. The bone marrow smears exhibited mild late-stage granulopoeitic defects. One patient developed myelodysplasia followed by acute myelogenous leukemia with translocation (18, 21) at age 14 years, cured by chemotherapy and hematopoietic stem cell transplantation. Four deaths occurred, including one from sepsis at age 5, one from pulmonary late-stage insufficiency at age 19, and two from sudden death, both at age 30 years. A new homozygous mutation (c.249G¿>¿A /p.Trp83*) was detected in one pedigree.ConclusionsSevere congenital neutropenia with autosomal recessive G6PC3 mutations is associated with considerable clinical heterogeneity. This series includes the first described case of malignancy in this neutropenia.
PMID: 25491320 [PubMed - as supplied by publisher]
Antiproliferative and proapoptotic effects of topotecan in combination with thymoquinone on acute myelogenous leukemia.
Clin Lymphoma Myeloma Leuk. 2014 Sep;14 Suppl:S46-55
Authors: Khalife R, Stephany el-H, Tarras O, Hodroj MH, Rizk S
BACKGROUND: Topotecan has shown promising antineoplastic activity in solid tumors and acute leukemia. Because of the primary dose-limiting toxicity of topotecan, it is necessary to identify other agents that can work synergistically with topotecan, potentially increasing its efficacy while limiting its toxicity. Many studies showed synergism in combination of topotecan with gemcitabine and bortezomib. Other studies report the increase in growth inhibition of gemcitabine or oxaliplatin when cells were preexposed to naturally occurring drugs such as thymoquinone. The aim of this project was to study the mode of action of topotecan along with thymoquinone, on survival and apoptosis pathways in acute myelogenous leukemia (AML) cell lines, and to investigate the potential synergistic effect of thymoquinone on topotecan.
MATERIALS AND METHODS: U937 cells were incubated with different topotecan and thymoquinone concentrations for 24 and 48 hours, separately and in combination. Cell proliferation was determined using WST-1 (Roche) reagent. The effect of the compounds on protein expression of Bax, Bcl2, p53, caspase-9, -8, and -3 was determined using Western blot analysis. Cell cycle analysis was performed in addition to annexin/propidium iodide staining.
RESULTS: Thymoquinone and topotecan exhibited antiproliferative effects on U937 cells when applied separately. In combination, the reduction in proliferation was extremely significant with a major increase in the expression levels of Bax/Bcl2, p53, and caspase-3 and -9. Preexposure with thymoquinone resulted in an increase in cell growth inhibition compared with topotecan treatment.
CONCLUSION: Thymoquinone, when combined with topotecan in noncytotoxic doses, produced synergistic antiproliferative and proapoptotic effects in AML cells. Preexposure to thymoquinone seems to be more effective than simultaneous application with topotecan.
PMID: 25486955 [PubMed - in process]
Allogeneic Stem Cell Transplant vs. Janus Kinase Inhibition in the Treatment of Primary Myelofibrosis or Myelofibrosis After Essential Thrombocythemia or Polycythemia Vera.
Clin Lymphoma Myeloma Leuk. 2014 Sep;14S:S36-S41
Authors: Alchalby H, Kröger N
Primary myelofibrosis is one of the Philadelphia chromosome-negative myeloproliferative neoplasms and is the member of that group with the worst survival and the most significant limitations in quality of life. Hepatosplenomegaly due to extramedullary hematopoiesis, constitutional symptoms, and cytopenias are the main manifestations. The natural history is highly variable, and up to 30% of patients can experience acceleration to acute myelogenous leukemia. Conventional therapy is only palliative and not always effective. However, huge advances have been achieved in the past 2 decades toward a better understanding of the pathogenesis of this disease, as well as improved management. Powerful risk stratification systems are now available and can reliably separate the patients into different prognostic categories to aid clinical management. Allogeneic stem cell transplant can offer cure but is still not universally applicable owing to the treatment-related mortality and toxicity. Nevertheless, outcomes of transplant are improving, owing to the introduction of reduced-intensity conditioning regimens and the optimization of remission monitoring techniques and relapse prevention strategies. The discovery of the V617F mutation of JAK2 (Janus kinase 2) and some other molecular aberrations has shed more light on the molecular pathogenesis of the disease and has led to the introduction of novel therapies such as JAK2 inhibitors. In fact, JAK inhibitors have shown promising symptomatic efficacy, and the JAK inhibitor ruxolitinib has also shown a potential survival benefit. Future effort should be made to combine allogeneic stem cell transplant with JAK inhibition.
PMID: 25486953 [PubMed - as supplied by publisher]
Phosphorylation of Ribosomal Protein S6 Kinase 1 at Thr421/Ser424 and Dephosphorylation at Thr389 Regulates SP600125-Induced Polyploidization of Megakaryocytic Cell Lines.
PLoS One. 2014;9(12):e114389
Authors: Li CL, Yang JG, Lin D, Zhao YS, Liu S, Xing SN, Zhao S, Chen CQ, Jiang ZM, Pu FF, Cao JP, Ma DC
Megakaryocytes (MKs) are one of the few cell types that become polyploid; however, the mechanisms by which these cells are designated to become polyploid are not fully understood. In this investigation, we successfully established two relatively synchronous polyploid cell models by inducing Dami and CMK cells with SP600125. We found that SP600125 induced the polyploidization of Dami and CMK cells, concomitant with the phosphorylation of ribosomal protein S6 kinase 1 (S6K1) at Thr421/Ser424 and dephosphorylation at Thr389. The polyploidization was partially blocked by H-89, a cAMP-dependent protein kinase (PKA) inhibitor, through direct binding to S6K1, leading to dephosphorylation at Thr421/Ser424 and phosphorylation at Thr389, independent of PKA. Overexpression of a rapamycin-resistant mutant of S6K1 further enhanced the inhibitory effect of LY294002 on the SP600125-induced polyploidization of Dami and CMK cells. SP600125 also induced the polyploidization of Meg-01 cells, which are derived from a patient with chronic myelogenous leukemia, without causing a significant change in S6K1 phosphorylation. Additionally, SP600125 induced the polyploidization of HEL cells, which are derived from a patient with erythroleukemia, and phosphorylation at Thr389 of S6K1 was detected. However, the polyploidization of both Meg-01 cells and HEL cells as a result of SP600125 treatment was lower than that of SP600125-induced Dami and CMK cells, and it was not blocked by H-89 despite the increased phosphorylation of S6K1 at Thr389 in both cell lines in response to H-89. Given that the Dami and CMK cell lines were derived from patients with acute megakaryocytic leukemia (AMKL) and expressed high levels of platelet-specific antigens, our data suggested that SP600125-induced polyploidization is cell-type specific, that these cell lines were more differentiated, and that phosphorylation at Thr421/Ser424 and dephosphorylation at Thr389 of S6K1 may play an important role in the SP600125-induced polyploidization of these cell lines synergistically with other signaling pathways.
PMID: 25486532 [PubMed - as supplied by publisher]
Acute myelogenous leukemia at Baylor Charles A. Sammons Cancer Center, 2010 to 2012: retrospective analysis of molecular genetic evaluation.
Proc (Bayl Univ Med Cent). 2014 Oct;27(4):299-304
Authors: Jones C, LeDay TV, Miller AM
Over the last several decades, advancements in the understanding of genetic and molecular origins of acute myeloid leukemia (AML) have brought about significant changes in how the disease is classified, diagnosed, and treated. The change from the traditional French-American-British classification system to that of the World Health Organization redefined how the disease is diagnosed not only morphologically but genetically. With genetic information proving to have prognostic value, the newer classification system, which incorporates results of cytogenetic and molecular analyses, allows better definition of disease and risk stratification, ultimately guiding treatment choices. As understanding and advancements in the molecular basis of AML continue to grow and influence patient management, the importance of an accurate and thorough initial patient evaluation is paramount. We performed a review of AML cases diagnosed at Baylor Charles A. Sammons Cancer Center from February 2010 to December 2012 to assess the thoroughness of initial diagnostic evaluations based on current guidelines, including up-to-date molecular analyses for mutations in NPM1, CEBPA, FLT3, and C-KIT. Results showed that patients newly diagnosed with AML undergo thorough diagnostic evaluation in keeping with current recommendations, and many had further genetic and molecular evaluations, which although considered optional or investigational, have prognostic significance. We identified potential areas of improvement for making this diagnostic evaluation more specific to the patient and the patient’s disease. Currently, we are investigating having patients undergo reflex genetic testing if they meet certain criteria to better define their specific disease while avoiding unnecessary genetic evaluations that come at increased cost.
PMID: 25484493 [PubMed - as supplied by publisher]
HS-543 induces apoptosis of Imatinib-resistant chronic myelogenous leukemia with T315I mutation.
Oncotarget. 2014 Dec 2;
Authors: Kim SJ, Jung KH, Yan HH, Son MK, Fang Z, Ryu YL, Lee H, Lim JH, Suh JK, Kim J, Lee S, Hong S, Hong SS
Chronic myeloid leukemia (CML) is characterized by a constitutive activation of Bcr-Abl tyrosine kinase. Bcr-Abl/T315I is the predominant mutation that causes resistance to Imatinib. In the present study, we synthesized a novel Bcr-Abl inhibitor, HS-543, and investigated its effect on cell survival or apoptosis in CML cells bearing Bcr-Abl/T315I (BaF3/T315I) or wild-type Bcr-Abl (BaF3/WT). HS-543 showed anti-proliferative effects in the BaF3/WT cells as well as the BaF3/T315I cells with resistance to Imatinib and strongly inhibited the Bcr-Abl signaling pathway in a dose-dependent manner. Furthermore, it significantly increased the sub G1 phase associated with early apoptosis, with increased levels of cleaved PARP and cleaved caspase-3, as well as the TUNEL-positive apoptotic cells. In addition, we found that HS-543 induced apoptosis with the loss of mitochondrial membrane potential by decreasing the expression of Mcl-1 and survivin, together with increasing that of Bax. In BaF3/T315I xenograft models, HS-543 significantly delayed tumor growth, unlike Imatinib. Our results demonstrate that HS-543 exhibits the induction of apoptosis and anti-proliferative effect by blocking the Bcr-Abl signaling pathway in the T315I-mutated Bcr-Abl cells with resistance to Imatinib. We suggest that HS-543 may be a novel promising agent to target Bcr-Abl and overcome Imatinib resistance in CML patients.
PMID: 25483100 [PubMed - as supplied by publisher]
Dasatinib reverses the multidrug resistance of breast cancer MCF-7 cells to doxorubicin by downregulating P-gp expression via inhibiting the activation of ERK signaling pathway.
Cancer Biol Ther. 2014 Nov 20;:0
Authors: Chen T, Wang C, Liu Q, Meng Q, Sun H, Huo X, Sun P, Peng J, Liu Z, Yang X, Liu K
Abstract Multidrug resistance (MDR) is one of the major obstacles to the efficiency of cancer chemotherapy, which often results from the overexpression of drug efflux transporters such as P-glycoprotein (P-gp). In the present study, we determined the effect of dasatinib which was approved for imatinib resistant chronic myelogenous leukemia (CML) and (Ph+) acute lymphoblastic leukemia (ALL) treatment on P-gp-mediated MDR. Our results showed that dasatinib significantly increased the sensitivity of P-gp-overexpressing MCF-7/Adr cells to doxorubicin in MTT assays; thus lead to an enhanced cytotoxicity of doxorubicin in MCF-7/Adr cells. Additionally, dasatinib increased the intracellular accumulation, inhibited the efflux of doxorubicin in MCF-7/Adr cells, and significantly enhanced doxorubicin-induced apoptosis in MCF-7/Adr cells. Further studies showed that dasatinib altered the expression levels of mRNA, protein levels of P-gp, and the phosphorylation of signal-regulated kinase (ERK) both in time-dependent (before 24 h) and dose-dependent manners at concentrations that produced MDR reversals. In conclusion, dasatinib reverses P-gp-mediated MDR by downregulating P-gp expression, which may be partly attributed to the inhibition of ERK pathway. Dasatinib may play an important role in circumventing MDR when combined with other conventional antineoplastic drugs.
PMID: 25482933 [PubMed - as supplied by publisher]
New treatment for acute myelogenous leukemia.
Expert Opin Pharmacother. 2014 Dec 5;:1-12
Authors: DiNardo CD, Cortes JE
Introduction: Acute myelogenous leukemia (AML) is a genetically heterogeneous disease. Yet current therapy has changed little over the decades and includes the nucleoside analog cytarabine in combination with an anthracycline as primary therapy. With this approach, durable cures occur in the minority of patients. With the recent improved scientific understanding of the underlying genetic and epigenetic aberrations in AML, there is now the potential of individualized and targeted therapeutic approaches for the curative treatment of AML. Areas covered: The focus of this article is to review the therapeutic potential of many of the novel agents currently under investigation in the treatment of acute myeloid leukemia. The results of pivotal Phase III studies, as well as ongoing Phase II and III studies and selected Phase I studies with impact on the field of AML therapy will be discussed. Expert opinion: Advances in the scientific knowledge of the various genetic and epigenetic alterations in AML, in conjunction with more effective, rationally designed and/or novel targeted therapeutics, offers a real hope and expectation of improved AML outcomes in the future.
PMID: 25480777 [PubMed - as supplied by publisher]
Population risk factor estimates for abdominal aortic aneurysm from electronic medical records: a case control study.
BMC Cardiovasc Disord. 2014 Dec 4;14(1):174
Authors: Smelser DT, Tromp G, Elmore JR, Kuivaniemi H, Franklin DP, Kirchner HL, Carey DJ
BACKGROUND: Using abdominal aortic aneurysm (AAA) as a model, this case-control study used electronic medical record (EMR) data to assess known risk factors and identify new associations.
METHODS: The study population consisted of cases with AAA (n =888) and controls (n =10,523) from the Geisinger Health System EMR in Central and Northeastern Pennsylvania. We extracted all clinical and diagnostic data for these patients from January 2004 to December 2009 from the EMR. From this sample set, bootstrap replication procedures were used to randomly generate 2,500 iterations of data sets, each with 500 cases and 2000 controls. Estimates of risk factor effect sizes were obtained by stepwise logistic regression followed by bootstrap aggregation. Variables were ranked using the number of inclusions in iterations and P values.
RESULTS: The benign neoplasm diagnosis was negatively associated with AAA, a novel finding. Similarly, type 2 diabetes, diastolic blood pressure, weight and myelogenous neoplasms were negatively associated with AAA. Peripheral artery disease, smoking, age, coronary stenosis, systolic blood pressure, age, height, male sex, pulmonary disease and hypertension were associated with an increased risk for AAA.
CONCLUSIONS: This study utilized EMR data, retrospectively, for risk factor assessment of a complex disease. Known risk factors for AAA were replicated in magnitude and direction. A novel negative association of benign neoplasms was identified. EMRs allow researchers to rapidly and inexpensively use clinical data to expand cohort size and derive better risk estimates for AAA as well as other complex diseases.
PMID: 25475588 [PubMed - as supplied by publisher]
Pattern of childhood leukaemia in University College Hospital, Ibadan.
Afr J Med Med Sci. 2014 Jun;43(2):135-8
Authors: Babatunde TO, Ogun GO, Brown BJ, Akang EE, Aken’Ova YA
BACKGROUND: Leukaemias are haematological malignancies characterized by unregulated clonal proliferation of haematopoietic cells.
OBJECTIVE: To determine the pattern of childhood leukaemia in Ibadan.
METHODOLOGY: This was a retrospective study of leukaemia cases diagnosed at the University College Hospital (UCH), Ibadan between January 1991 and December 2010 in children less than 15 years of age. Data obtained was subjected to statistical analysis using the Statistical Package for Social Sciences version 20.
RESULTS: There were 64 cases of childhood leukaemia, accounting for 10.2% of childhood cancers seen during this study period. The male to female ratio was 2:1 and modal age group was between 10 and 14 years. Thirty (46.9%) cases were acute lymphoblastic leukaemia (ALL), 22 (34.4%) were acute myelogenous leukaemia (AML) and 12 (18.8%) were unspecified acute leukaemias. There was no case of chronic myeloid or lymphocytic leukaemia.
CONCLUSION: There has been a relative increase in the frequency of leukaemia cases at UCH, Ibadan, which may be largely explained by increased awareness and referrals. There is a need for further collaborative multicentre studies of childhood leukaemias in Nigeria and other developing countries and focused research on childhood leukaemias in order to unravel the aetiology.
PMID: 25474988 [PubMed - in process]
New Benzimidazole-Derived Isothioureas as Potential Antileukemic Agents – Studies In Vitro.
Med Chem. 2014 Dec 3;
Authors: Koronkiewicz M, Romiszewska A, Chilmonczyk Z, Kazimierczuk Z
Isothioureas are a class of amphiphilic compounds carrying a highly basic isothiourea group of pKa ranging between 10 and 11. Hence, they exist in protonated (cation) form at physiological pH, a characteristic is of key importance for their pharmacological activity. Recently, we have found that a number of S-pentabromobenzylisothiourea derivatives show substantial cytotoxicity toward a variety of human glioblastoma, leukemia, and adenocarcinoma cell lines. Whereas there is a growing body of data on aliphatic and alkylaromatic isothioureas, little attention was given to this day to heterocyclic isotiourea derivatives. Here we report on the synthesis and pharmacological in vitro properties of 10 novel S-(benzimidazol-2-ylmethyl)- and S-(5,6-dichlorobenzimidazol-2-ylmethyl)isothiourea derivatives. The compounds were obtained by the condensation of the respective 2-chloromethyl benzimidazoles with various substituted N(N’)-thioureas. Besides the essential physicochemical characteristics (H-NMR, UV, elemental analysis) of the new compounds, their log P values, which are of key importance for in vivo drug distribution and interactions, were determined. Pharmacological (anticancer) activity of the compounds was evaluated based on their ability to induce apoptosis in exponentially growing cultures of the human acute myelogenous leukemia cell line KG-1; the apoptosis was assessed with a variety of flow cytometric methods. Of the novel compounds tested, the most potent apoptosis inducer in KG-1 cells was N-methyl-S-(5,6-dichloro-1H-benzimidazol-2-ylmethyl)isothiouronium chloride (ClBMMe).
PMID: 25470504 [PubMed - as supplied by publisher]