Chronic Myeloid Leukemia Therapy: Focus on Second-Generation Tyrosine Kinase Inhibitors

McFarland, Katherine; Wetzstein, Gene A.

doi:10.1177/107327480901600205

Cited by 17 publications

(13 citation statements)

References 45 publications

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“…Nilotinib, an analog of imatinib, has higher selectivity to BCR-ABL as compared to imatinib. Nilotinib disrupts the ATP binding pocket of BCR-ABL tyrosine kinase and inhibits enzymatic activity by binding to the inactive conformation of the protein and by blocking its interaction with target proteins [13]. Nilotinib can be used both alone [14] and in combination with other agents for the treatment of CML.…”

Section: Introductionmentioning

confidence: 99%

Roles of ceramide synthase and ceramide clearence genes in nilotinib-induced cell death in chronic myeloidleukemia cells

Camgöz

Gençer

Ural

et al. 2011

Leukemia & Lymphoma

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In this study, we aimed to increase the sensitivity of human K562 and Meg-01 chronic myeloid leukemia (CML) cells to nilotinib by targeting bioactive sphingolipids, in addition to investigating the roles of ceramide metabolizing genes in nilotinib induced apoptosis. Cytotoxic effects of nilotinib, C8:ceramide, glucosyle ceramide synthase (GCS) and sphingosine kinase-1 (SK-1) inhibitors were determined by XTT cell proliferation assay and synergism between the agents was determined by isobologram analysis. Also, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) results demonstrated that expression levels of longevity assurance (LASS) genes in response to nilotinib were correlated with sensitivity to nilotinib. For the first time, The results of this study showed for the first time that nilotinib induces apoptosis through upregulating ceramide synthase genes and downregulating SK-1 in CML cells in addition to inhibition of BCR/ABL. On the other hand, manipulating bioactive sphingolipids toward generation/accumulation of ceramides increased the apoptotic effects of nilotinib in CML cells.

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Section: Introductionmentioning

confidence: 99%

Roles of ceramide synthase and ceramide clearence genes in nilotinib-induced cell death in chronic myeloidleukemia cells

Camgöz

Gençer

Ural

et al. 2011

Leukemia & Lymphoma

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“…Of these, dasatinib, an orally active, small molecule that inhibits Bcr-Abl, along with multiple other kinases including the SRC family kinases (Guilhot et al, 2007) and nilotinib (Tasigna; Novartis Pharmaceuticals, Basel, Switzerland), a phenyl aminopyrimidine analogue of imatinib, have recently been approved by the FDA for treatment of imatinib-resistant CML patients (McFarland and Wetzstein, 2009). Although these second-generation tyrosine kinase inhibitors are effective against many Bcr-Abl mutants, they are completely ineffective against the T315I mutants.…”

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confidence: 99%

Novel pyrrolo-1,5-benzoxazepine compounds display significant activity against resistant chronic myeloid leukaemia cells in vitro, in ex vivo patient samples and in vivo

et al. 2010

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BACKGROUND: Imatinib is a direct and potent inhibitor of the constitutively active tyrosine kinase, breakpoint cluster region-Abelson (Bcr-Abl), which is central to the pathogenesis of chronic myeloid leukaemia (CML) patients. As such, imatinib has become the frontline treatment for CML patients. However, the recent emergence of imatinib resistance, commonly associated with point mutations within the kinase domain, has led to the search for alternative drug treatments and combination therapies for CML. METHODS: In this report, we analyse the effects of representative members of the novel pro-apoptotic microtubule depolymerising pyrrolo-1,5-benzoxazepines or PBOX compounds on chemotherapy-refractory CML cells using a series of Bcr-Abl mutant cell lines, clinical ex vivo patient samples and an in vivo mouse model. RESULTS: The PBOX compounds potently reduce cell viability in cells expressing the E225K and H396P mutants as well as the highly resistant T315I mutant. The PBOX compounds also induce apoptosis in primary CML samples including those resistant to imatinib. We also show for the first time, the in vivo efficacy of the pro-apoptotic PBOX compound, PBOX-6, in a CML mouse model of the T315I Bcr-Abl mutant. CONCLUSION: Results from this study highlight the potential of these novel series of PBOX compounds as an effective therapy against CML.

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“…Second-generation Bcr-Abl inhibitors (nilotinib and dasatinib) are now available for patients intolerant of IM or with IM-refractory disease, and these agents have already shown improved activity in patients with acquired mutations [17]. Compounds with activity in vitro against the cross-resistant Bcr-Abl (T315I) mutation have been described [18].…”

Section: What To Target and How To Targetmentioning

confidence: 98%

Targeting Chronic Myeloid Leukemia Stem Cells

Helgason

Young

Holyoake

2010

Curr Hematol Malig Rep

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Chronic myeloid leukemia (CML) arises as a consequence of a chromosomal translocation giving rise to the Philadelphia chromosome and Bcr-Abl oncogene. CML is a clonal disease of stem cell origin and an excellent example of a malignancy in which tumor-initiating cells may hold the key to disease eradication. The known molecular basis of CML has enabled the development of Abl-specific tyrosine kinase inhibitors, such as imatinib mesylate. However, the success of tyrosine kinase inhibitors, as rationally designed first-line therapies, has been tempered by problems of disease persistence and resistance. Residual disease has been shown to be enriched within the stem cell compartment and to persist at stable levels for up to 5 years of complete cytogenetic response. This finding has led to further searches for novel strategies aimed at eliminating these cells; such strategies may be essential in achieving cure. The most significant recent findings are discussed in this review.

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Chronic Myeloid Leukemia Therapy: Focus on Second-Generation Tyrosine Kinase Inhibitors

Cited by 17 publications

References 45 publications

Roles of ceramide synthase and ceramide clearence genes in nilotinib-induced cell death in chronic myeloidleukemia cells

Roles of ceramide synthase and ceramide clearence genes in nilotinib-induced cell death in chronic myeloidleukemia cells

Novel pyrrolo-1,5-benzoxazepine compounds display significant activity against resistant chronic myeloid leukaemia cells in vitro, in ex vivo patient samples and in vivo

Targeting Chronic Myeloid Leukemia Stem Cells

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