Abstract:
:HSP90 is a multi-client chaperone involved in regulating a large array of cellular processes and is commonly overexpressed in many different cancer types including hematological malignancies. Inhibition of HSP90 holds promise for targeting multiple molecular abnormalities and is therefore an attractive target for heterogeneous malignancies such as Acute Myeloid Leukemia (AML). Ganetespib is a highly potent second generation HSP90 inhibitor which we show is significantly more effective against primary AML blasts at nanomolar concentrations when compared with cytarabine (p<0.001). Dose dependant cytotoxicity was observed with an apoptotic response coordinate with the loss of pro-survival signaling through the client protein AKT. Combination treatment of primary blasts with ganetespib and cytarabine showed good synergistic interaction (combination index (CI): 0.47) across a range of drug effects with associated reduction in HSP70 feedback and AKT signaling levels. In summary, we show ganetespib to have high activity in primary AMLs as a monotherapy and a synergistic relationship with cytarabine when combined. The combination of cytotoxic cell death, suppression of cytoprotective/drug resistance mechanisms such as AKT and reduced clinical toxicity compared to other HSP90 inhibitors provide strong rationale for the clinical assessment of ganetespib in AML.
journal_name
Leuk Resjournal_title
Leukemia researchauthors
Lazenby M,Hills R,Burnett AK,Zabkiewicz Jdoi
10.1016/j.leukres.2015.03.016subject
Has Abstractpub_date
2015-06-01 00:00:00pages
617-24issue
6eissn
0145-2126issn
1873-5835pii
S0145-2126(15)00087-9journal_volume
39pub_type
杂志文章abstract::The revised IPSS (IPSS-R) was developed aiming at a better prognostication, taking into account patients treated with best supportive care. We herein validated this model on the basis of data from 1314 patients who received BSC only as well as patients who underwent induction chemotherapy (n=214) or allogeneic transpl...
journal_title:Leukemia research
pub_type: 杂志文章,多中心研究
doi:10.1016/j.leukres.2013.10.013
更新日期:2014-01-01 00:00:00
abstract::Leukaemic cells from the peripheral blood of 90 patients with acute leukaemia (54 non-lymphocytic (ANLL) 36 lymphocytic (ALL)) have been examined for the presence of the platelet/ALL-associated p24 membrane antigen by indirect immunofluorescence and flow cytometry using monoclonal antibody FMC8. Cells from 28 of the A...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/0145-2126(87)90109-3
更新日期:1987-01-01 00:00:00
abstract:BACKGROUND:The median survival of patients with chronic myelogenous leukemia in myeloid blast crisis (MBC-CML) is poor even for patients treated with tyrosine kinase inhibitors (TKIs). DESIGN AND METHODS:We conducted a dose-escalating study of daunorubicin combined to fixed doses of IM (imatinib mesylate, 600 mg/d) an...
journal_title:Leukemia research
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1016/j.leukres.2010.11.004
更新日期:2011-06-01 00:00:00
abstract::Acute monocytic leukemia (M5) is a subtype of acute myeloid leukemia (AML) with two distinct morphologic subcategories, M5a and M5b. We compared the immunophenotype, cytogenetics and clinical outcome of AML M5 with non-M5 AML and also compared M5a with M5b. One hundred and twelve M5 (76 M5a, 36 M5b) and 726 non-M5 cas...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/j.leukres.2007.06.019
更新日期:2008-02-01 00:00:00
abstract::It has become routine practice to culture bone marrow and/or unstimulated peripheral blood for cytogenetic analysis due to associations of consistent chromosomal abnormalities within specific subgroups of leukemias. Unfortunately, two leukemias for which numerous chromosomal aberrations have been recorded, acute myelo...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/0145-2126(89)90085-4
更新日期:1989-01-01 00:00:00
abstract::Acute promyelocytic leukemia (APL) is characterized by a reciprocal translocation, t(15;17) (q22;q12), resulting in fusion of the genes promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARA). With conventional cytogenetic methods, these translocations are detected in about 70-90% of patients, with most o...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/j.leukres.2006.05.011
更新日期:2007-02-01 00:00:00
abstract::We have studied the survival of clonogenic neoplastic cells of a murine pre-B-lymphoma (BCl-1) of the spleen in culture. We have found quantitative deficiencies such as reduced surface adherence of stromal cells and impaired CFU-F (colony forming units-fibroblast) and pre-CFU-F colony and layer formation in stromal cu...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/0145-2126(93)90088-3
更新日期:1993-07-01 00:00:00
abstract::Higher-risk myelodysplastic syndromes (MDS) are rarely curable and have a poor prognosis. We investigated the accuracy of physicians' perception of patients' health status and the patients' preferences for involvement in treatment decisions. We examined 280 newly diagnosed higher-risk elderly MDS patients paired with ...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/j.leukres.2015.05.012
更新日期:2015-08-01 00:00:00
abstract::We examined the symptoms and referral rates to specialized palliative care and psychosocial oncology services of patients with acute leukemia. The Memorial Symptom Assessment Scale (MSAS) was completed by 249 adult patients with acute leukemia. Patients reported a median of 9 physical and 2 psychological symptoms, and...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/j.leukres.2013.02.009
更新日期:2013-07-01 00:00:00
abstract::CFW/D mice injected neonatally with a type B retrovirus, (DMBA-LV), rapidly develop thymic lymphomas. The present study examined simultaneously the karyotype and the expression of surface antigens on thymocytes from DMBA-LV treated mice at 28, 35 and 42 days of age during the development of lymphomas, and of cells fro...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/0145-2126(89)90122-7
更新日期:1989-01-01 00:00:00
abstract::3q26.2/EVI1 rearrangements resulting in EVI1 overexpression play an important role in leukemogenesis and are associated with treatment resistance and a poorer prognosis in patients with acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia and BCR-ABL negative myeloproliferative neoplasms. In this...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/j.leukres.2017.12.004
更新日期:2018-02-01 00:00:00
abstract::The aim of this study was to evaluate effect of c-KIT mutations on RUNX1/RUNX1T1 fusion transcript expression in patients with t(8;21)-positive AML. Fifty patients diagnosed with t(8;21)-positive AML for recent 10 years were enrolled. Patients with c-KIT mutations tended to achieve a greater than 3-log reduction in RU...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/j.leukres.2013.02.010
更新日期:2013-07-01 00:00:00
abstract::Induction of granulocyte maturation in HL-60 leukemic cells by DMSO (1.2%) or RA (1 microM) is accompanied by a 50-60% decrease in cellular thymidine kinase activity. Similarly, the differentiation of HL-60 cells into monocyte-macrophage phenotype by the addition of PMA is paralleled by a 60-80% suppression of thymidi...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/0145-2126(87)90079-8
更新日期:1987-01-01 00:00:00
abstract::MEK/ERK signal pathway was required for the differentiation of granulocytes, megakaryocytes and erythrocytes. Recently, MEK/ERK cascade was reported to be involved in all-trans retinoic acid (ATRA) induced differentiation in acute promyelocytic leukemia (APL) cells. However, the upstream and downstream molecules of ME...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/j.leukres.2016.03.008
更新日期:2016-06-01 00:00:00
abstract::Five patients from the Kyushu area in Japan with adult T-cell leukaemia (ATL) refractory to conventional chemotherapeutic agents were treated with 5 mg/m2 of the adenosine deaminase inhibitor, 2'-deoxycoformycin (DCF), intravenously (i.v.) for 3 consecutive days, followed by 5 mg/m2 i.v. weekly. Two patients showed a ...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/0145-2126(86)90251-1
更新日期:1986-01-01 00:00:00
abstract::Thermal stress induces expression of a family of heat shock proteins which may regulate the synthesis of various cellular genes. We investigated the effect of heat shock on polyadenylation in Epstein-Barr Virus (EBV) negative and EBV transformed human Burkitt's lymphoma (BL) B-cell lines. Incubation of the BL B-cell l...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/0145-2126(95)00063-1
更新日期:1995-11-01 00:00:00
abstract::We have previously shown that HL-60 cells exposed to all-trans retinoic acid (ATRA) after treatment with a non-cytotoxic concentration of vincristine (VCR) result in granulocytic maturation and differentiation, suggesting that VCR might exhibit a synergistic action with ATRA in the treatment of acute promyelocytic leu...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/s0145-2126(96)00090-2
更新日期:1997-01-01 00:00:00
abstract::The functional behavior of hematopoietic stem cell (HSC) and progenitors in chronic myelomonocytic leukemia (CMML) and on disease progression is little known. We performed cell proliferation, apoptosis, hematopoietic colony forming/replating and differentiation potential studies in the purified subpopulations of Lin(-...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/j.leukres.2008.02.011
更新日期:2008-09-01 00:00:00
abstract::Occupational and industrial exposures have been implicated in the etiology of leukemia, yet uncertainty remains regarding potential high risk occupations. We examined the associations between self-reported occupations and hobbies and acute leukemia risk using data from 811 cases and 637 controls participating in a cas...
journal_title:Leukemia research
pub_type: 杂志文章,多中心研究
doi:10.1016/j.leukres.2005.03.002
更新日期:2005-10-01 00:00:00
abstract::The direct effect of the feline leukaemia virus (FeLV) on erythroid colony formation in vitro was investigated. Bone marrow mononuclear cells (BMMC) from FeLV-naïve, specific-pathogen-free (SPF), adult cats were inoculated with FeLVs of characterized strains and biologically cloned subgroups and the subsequent develop...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/0145-2126(86)90237-7
更新日期:1986-01-01 00:00:00
abstract::Although verapamil, cyclosporin A. cremophor EL and PSC-833 are active as multidrug resistance modulators, there has been limited study of these compounds as possible chemotherapy enhancing agents against drug-sensitive tumors. We compared these agents as modifiers of VP-16 cytotoxicity in vitro and modifiers of VP-16...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/0145-2126(95)00029-n
更新日期:1995-08-01 00:00:00
abstract::Imatinib mesylate (IM) is the treatment of choice in patients with newly diagnosed chronic myeloid leukemia (CML), irrespectively of their age. Nevertheless, information regarding tolerability and responses in advanced-age patients, a subgroup in which co-morbidities and other factors may influence outcome, is scarce,...
journal_title:Leukemia research
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1016/j.leukres.2011.01.017
更新日期:2011-09-01 00:00:00
abstract::Changes of phosphoprotein patterns in HL-60 cells were studied during short exposures to 1 alpha, 25-dihydroxyvitamin D3 [1,25(OH)2D3]. One hundred nanometers 1,25(OH)2D3 dephosphorylated at least three proteins in 6 h: phosphoproteins with molecular weights of 82 kD (pp82), 33 kD (pp33), and 31 kD (pp31). Phosphoryla...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/0145-2126(91)90169-t
更新日期:1991-01-01 00:00:00
abstract::The thymic stroma has long been implicated in AKR thymic leukaemia. In this study an extensive panel of monoclonal antibodies was used to investigate changes in the AKR thymic microenvironment, in parallel with thymocyte differentiation of normal (2 month), preleukaemic (5-7 month) and leukaemic (> 7 month) mice. We f...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/0145-2126(95)00102-6
更新日期:1996-10-01 00:00:00
abstract::Activating mutations or over-expression of the Flt3 is prevalent in acute myeloblastic leukemia (AML), associated with activation of Ras/MAP kinase and other signaling pathways. In this study, we addressed the role of Flt3 in the activation of nuclear factor-kappa B (NF-kappaB), which is a target molecule of these kin...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/j.leukres.2005.01.008
更新日期:2005-08-01 00:00:00
abstract::The National Comprehensive Cancer Network (NCCN) defines the following types of acute myeloid leukemia (AML) as favorable-risk: acute promyelocytic leukemia with t(15;17) (APL); AML with core-binding factor (CBF) rearrangements, including t(8;21) and inv(16) or t(16;16) without mutations in KIT (CBF-KITwt); and AML wi...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/j.leukres.2017.12.012
更新日期:2018-02-01 00:00:00
abstract::To determine the incidence of haematological malignancies in French Polynesia from 1990 to 1995, we collected cases from the local cancer registry, sanitary evacuation files and all the histopathology and clinical biology laboratories. All leukaemias, non Hodgkin's lymphomas, and multiple myelomas incidence was slight...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/s0145-2126(98)00186-6
更新日期:1999-04-01 00:00:00
abstract::Normal human peripheral blood polymorphonuclear leukocytes (PMNs) and cells from a human acute promyelocytic leukemia line (HL-60) were tested for cytotoxic potential against two human glioma and one normal fibroblast line. Both the PMNs and HL-60 exhibited significant cytotoxicity against the tumor targets while spar...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/0145-2126(84)90101-2
更新日期:1984-01-01 00:00:00
abstract::The capacity of human thymocytes and of differentiated lymphocytes circulating in peripheral blood to perform unscheduled DNA synthesis (a measure of nucleotide excision repair) after UV irradiation was measured by radioautographic analysis. Only 4% of immature T lymphocytes, but 68% of circulating lymphocytes exhibit...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/0145-2126(85)90006-2
更新日期:1985-01-01 00:00:00
abstract::Like CD19 or CD56, CD22 in non-lymphoid leukemia has been considered an aberrantly expressed antigen. CD22 had been believed to be restricted to B lymphoid, however, it was also found to be expressed in human basophils. Mature basophils are unique granulocytes expressing CD13, CD22 and CD25. To estimate whether the ex...
journal_title:Leukemia research
pub_type: 杂志文章
doi:10.1016/j.leukres.2003.10.034
更新日期:2004-07-01 00:00:00