FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W138505280> ?p ?o ?g. }

• W138505280 abstract "Abstract The advent of tyrosine kinase inhibitors (TKI) that specifically target BCR-ABL has significantly prolonged the life of patients with CML. We and others have previously shown that the BH3 mimetic ABT-737 or its clinical equivalent, ABT-263, can significantly enhance TKI-induced cell death in both CML cell lines and primary cells (Ng et al. Nature Medicine, 18: 521-528, 2012). ABT-737 and ABT-263 are BH3 mimetics that have broad specificity against anti-apoptosis regulators such as BCL-2 and its related proteins (BCL-XL & BCL-W). However, in clinical trials employing ABT-263, a dose-limiting toxicity is thrombocytopenia. This is due to the inhibitory effect of ABT-263 on BCL-XL that is pivotal for platelet survival. As a result, a new BH3 mimetic, ABT-199, has been developed that binds with high affinity to BCL-2 but not BCL-XL, and thus does not harm platelets. Here, we evaluated the effectiveness of ABT-199, as a single agent or in combination with imatinib, in reducing the viability of CD34+ cells from the different phases of CML (chronic, accelerated and blast). We also assessed the cytotoxic effect of ABT-199 on normal cord blood CD34+ cells. The number of samples used in this study was: (1) chronic phase CML (CP, n=4), (2) accelerated phase CML (AP, n=2), (3) blast phase CML (BP, n=1), and (4) normal cord blood (NCB, n=3). We evaluated the viability of progenitor cells by colony formation assay. A broad concentration range of ABT-199 (in nM: 0, 1, 2, 5, 10, 20, 50, 100, 200, 500, 2000) was used in this study. The concentration of imatinib used was 2uM, which is in line with the plasma concentrations achievable in most patients with CML. Below are three tables that summarize the results obtained from this study.Table 1Treatment with 2uM imatinib only.CP (n=4)AP & BC (n=3)NCB (n=3)Average CFU reduction65%23%20%(Relative to DMSO control)Table 2Treatment with ABT-199 only: concentration required to achieve the following CFU reduction.Average CFU reductionCP (n=4)AP & BC (n=3)NCB (n=3)50%500nM2000nM10nM90%2000nMNot achieved within the concentration range used500nMTable 3Combined treatment with ABT-199 and 2uM imatinib (IM): concentration required to achieve the following CFU reduction.Average CFU reductionCP (n=4)AP & BC (n=3)NCB (n=3)50%Not achieved within the concentration range used2nM ABT-199 + 2uM IM10nM ABT-199 + 2uM IM90%10nM ABT-199 + 2uM IM200nM ABT-199 + 2uM IM100nM ABT-199 + 2uM IM In summary, we found that: (1) Compared to CML, NCB progenitors were very sensitive to ABT-199, with a reduction of average cell viability to 50% at just 10nM (with or without imatinib); (2) When the dose-limiting cytotoxic effect of ABT-199 on NCB was taken into consideration, we were able to discover an ABT-199 concentration (10nM) that significantly enhanced imatinib-induced cell death of CP CML progenitors without causing NCB viability to fall below 50%; and (3) The inferior efficacy of the combination on AP/BC vs CP progenitors suggests that BCL2-independent mechanisms contribute to the survival of advanced phase CML progenitors. Finally, our in vitro data may also explain some of the adverse hematologic effects observed in clinical trials that employ ABT-199, including neutropenia and thrombocytopenia. Nevertheless, our data suggest that ABT-199, when used at a concentration that is not cytotoxic to normal progenitors and in combination with imatinib, can be beneficial in treating patients with chronic phase CML. Disclosures: Chuah: Novartis: Honoraria; Bristol-Myers Squibb: Honoraria." @default.
• W138505280 created "2016-06-24" @default.
• W138505280 creator A5020288289 @default.
• W138505280 creator A5055510705 @default.
• W138505280 creator A5055961417 @default.
• W138505280 creator A5061597777 @default.
• W138505280 creator A5078535679 @default.
• W138505280 date "2013-11-15" @default.
• W138505280 modified "2023-10-02" @default.
• W138505280 title "The BCL-2 Inhibitor ABT-199 Enhances Imatinib-Induced Cell Death In Chronic Phase CML Progenitors" @default.
• W138505280 doi "https://doi.org/10.1182/blood.v122.21.3978.3978" @default.
• W138505280 hasPublicationYear "2013" @default.
• W138505280 type Work @default.
• W138505280 sameAs 138505280 @default.
• W138505280 citedByCount "1" @default.
• W138505280 countsByYear W1385052802021 @default.
• W138505280 crossrefType "journal-article" @default.
• W138505280 hasAuthorship W138505280A5020288289 @default.
• W138505280 hasAuthorship W138505280A5055510705 @default.
• W138505280 hasAuthorship W138505280A5055961417 @default.
• W138505280 hasAuthorship W138505280A5061597777 @default.
• W138505280 hasAuthorship W138505280A5078535679 @default.
• W138505280 hasConcept C10205521 @default.
• W138505280 hasConcept C109159458 @default.
• W138505280 hasConcept C137061746 @default.
• W138505280 hasConcept C185592680 @default.
• W138505280 hasConcept C190283241 @default.
• W138505280 hasConcept C201750760 @default.
• W138505280 hasConcept C202751555 @default.
• W138505280 hasConcept C203014093 @default.
• W138505280 hasConcept C2777583451 @default.
• W138505280 hasConcept C2778729363 @default.
• W138505280 hasConcept C2780914630 @default.
• W138505280 hasConcept C28328180 @default.
• W138505280 hasConcept C3019892230 @default.
• W138505280 hasConcept C502942594 @default.
• W138505280 hasConcept C53227056 @default.
• W138505280 hasConcept C55493867 @default.
• W138505280 hasConcept C71924100 @default.
• W138505280 hasConcept C86803240 @default.
• W138505280 hasConcept C95444343 @default.
• W138505280 hasConcept C98274493 @default.
• W138505280 hasConceptScore W138505280C10205521 @default.
• W138505280 hasConceptScore W138505280C109159458 @default.
• W138505280 hasConceptScore W138505280C137061746 @default.
• W138505280 hasConceptScore W138505280C185592680 @default.
• W138505280 hasConceptScore W138505280C190283241 @default.
• W138505280 hasConceptScore W138505280C201750760 @default.
• W138505280 hasConceptScore W138505280C202751555 @default.
• W138505280 hasConceptScore W138505280C203014093 @default.
• W138505280 hasConceptScore W138505280C2777583451 @default.
• W138505280 hasConceptScore W138505280C2778729363 @default.
• W138505280 hasConceptScore W138505280C2780914630 @default.
• W138505280 hasConceptScore W138505280C28328180 @default.
• W138505280 hasConceptScore W138505280C3019892230 @default.
• W138505280 hasConceptScore W138505280C502942594 @default.
• W138505280 hasConceptScore W138505280C53227056 @default.
• W138505280 hasConceptScore W138505280C55493867 @default.
• W138505280 hasConceptScore W138505280C71924100 @default.
• W138505280 hasConceptScore W138505280C86803240 @default.
• W138505280 hasConceptScore W138505280C95444343 @default.
• W138505280 hasConceptScore W138505280C98274493 @default.
• W138505280 hasLocation W1385052801 @default.
• W138505280 hasOpenAccess W138505280 @default.
• W138505280 hasPrimaryLocation W1385052801 @default.
• W138505280 hasRelatedWork W231973258 @default.
• W138505280 hasRelatedWork W2332180477 @default.
• W138505280 hasRelatedWork W2340300548 @default.
• W138505280 hasRelatedWork W2522873693 @default.
• W138505280 hasRelatedWork W2550959716 @default.
• W138505280 hasRelatedWork W2551380011 @default.
• W138505280 hasRelatedWork W2552244767 @default.
• W138505280 hasRelatedWork W2566505248 @default.
• W138505280 hasRelatedWork W2577290629 @default.
• W138505280 hasRelatedWork W2577884059 @default.
• W138505280 hasRelatedWork W2585746906 @default.
• W138505280 hasRelatedWork W2585845032 @default.
• W138505280 hasRelatedWork W2586567488 @default.
• W138505280 hasRelatedWork W2594665693 @default.
• W138505280 hasRelatedWork W2901321510 @default.
• W138505280 hasRelatedWork W2979471830 @default.
• W138505280 hasRelatedWork W2980032444 @default.
• W138505280 hasRelatedWork W2980245895 @default.
• W138505280 hasRelatedWork W65177702 @default.
• W138505280 hasRelatedWork W68676002 @default.
• W138505280 isParatext "false" @default.
• W138505280 isRetracted "false" @default.
• W138505280 magId "138505280" @default.
• W138505280 workType "article" @default.