Phase II Study of Low-Dose Decitabine in Patients With Chronic Myelogenous Leukemia Resistant to Imatinib Mesylate

Issa, Jean–Pierre J.; Gharibyan, Vazganush; Cortes, Jorge; Jelı́nek, Jaroslav; Morris, Gail; Verstovšek, Srđan; Talpaz, Moshe; Garcia‐Manero, Guillermo; Kantarjian, Hagop M.

doi:10.1200/jco.2005.11.981

Cited by 283 publications

(201 citation statements)

References 23 publications

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“…Both drugs are particularly effective when administered at low doses, which are sometimes below 10% of their maximum tolerated doses (Issa and Kantarjian, 2009). These conditions are generally assumed to maximize DNA demethylation responses, and several studies have confirmed that drug-induced DNA demethylation occurs in patients (Issa et al, 2005;Mund et al, 2005;Soriano et al, 2007;Stresemann and Lyko, 2008). However, a direct link between DNA demethylation and clinical responses has not been demonstrated yet and there are currently no established DNA methylation biomarkers that accurately predict patient responses (Fandy et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic cancer therapy: rationales, targets and drugs

2011

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The fundamental role of altered epigenetic modification patterns in tumorigenesis establishes epigenetic regulatory enzymes as important targets for cancer therapy. Over the past few years, several drugs with an epigenetic activity have received approval for the treatment of cancer patients, which has led to a detailed characterization of their modes of action. The results showed that both established drug classes, the histone deacetylase (HDAC) inhibitors and the DNA methyltransferase inhibitors, show substantial limitations in their epigenetic specificity. HDAC inhibitors are highly specific drugs, but the enzymes have a broad substrate specificity and deacetylate numerous proteins that are not associated with epigenetic regulation. Similarly, the induction of global DNA demethylation by non-specific inhibition of DNA methyltransferases shows pleiotropic effects on epigenetic regulation with no apparent tumor-specificity. Second-generation azanucleoside drugs have integrated the knowledge about the cellular uptake and metabolization pathways, but do not show any increased specificity for cancer epigenotypes. As such, the traditional rationale of epigenetic cancer therapy appears to be in need of refinement, as we move from the global inhibition of epigenetic modifications toward the identification and targeting of tumor-specific epigenetic programs. Recent studies have identified epigenetic mechanisms that promote self-renewal and developmental plasticity in cancer cells. Druggable somatic mutations in the corresponding epigenetic regulators are beginning to be identified and should facilitate the development of epigenetic therapy approaches with improved tumor specificity.

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Section: Introductionmentioning

confidence: 99%

Epigenetic cancer therapy: rationales, targets and drugs

2011

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“…Indeed, 5-aza-2 0 -deoxycitidine has been shown to have clinical activity in imatinib resitant CML. 27 The role of Hck inactivation in imatinib resistance therefore needs further studies.…”

Section: Discussionmentioning

confidence: 99%

Aberrant DNA methylation of the Src kinase Hck, but not of Lyn, in Philadelphia chromosome negative acute lymphocytic leukemia

et al. 2007

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Hck and Lyn are required in Philadelphia chromosome (Ph) positive acute lymphocytic leukemia (ALL). Here, we present evidence that the promoter CpG island of Hck, but not of Lyn, is aberrantly methylated in leukemia. Hck promoter DNA methylation was detected in 13 out of 23 (56.5%) hematopoietic and eight out of 10 (80%) non-hematopoietic cell lines, but not in normal controls. Treatment with 5-aza-2 0 -deoxycytidine induced demethylation and restoration of Hck mRNA and protein expression. Hck methylation (X15%) was detected in nine out of 44 (20%) patients with Ph negative ALL, and in one out 16 (6%) patients with Ph positive ALL, but not in patients with AML or chronic myelogenous leukemia. In this subset of patients, low levels of Hck methylation (10-15%) were observed in 26-30% of patients. Lyn methylation was observed in three out of 28 (10.7%) cell lines, but only in one out of 71 (1.4%) patients. Patients with Ph negative ALL and Hck methylation had a poorer prognosis. These data indicate that Hck may have tumor suppressor properties in BCR-ABL negative leukemia. Leukemia (2007) 21, 906-911.

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“…No reports described hypermethylation of any of the STAT regulators in CML. However, in line with the promising results following treatment with decitabine in patients with imatinib-resistant disease [77], it may be justified to further study the genes to be hypomethylated.…”

Section: Hypermethylation Of Stat Inhibitors In Chronic Leukemiasmentioning

confidence: 99%

Epigenetic regulation of signal transducer and activator of transcription 3 in acute myeloid leukemia

2008

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We have demonstrated that constitutive signal transducer and activator of transcription (STAT) 3 activity, observed in approximately 50% of acute myeloid leukemia (AML) cases, is associated with adverse treatment outcome. Constitutive STAT3 activation may result from the expression of oncogenic protein tyrosine kinases or from autocrine stimulation by hematopoietic growth factors. These causes are generally neither necessary nor sufficient for leukemogenesis; additional transforming events or growth stimulatory processes are needed. Here we review the literature addressing epigenetic regulation as a mechanism controlling STAT3 signaling in AML. A better understanding of mechanisms of dysregulation of STAT signaling pathways may serve as a basis for designing novel therapeutic strategies that target these pathways in leukemia cells.

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Phase II Study of Low-Dose Decitabine in Patients With Chronic Myelogenous Leukemia Resistant to Imatinib Mesylate

Cited by 283 publications

References 23 publications

Epigenetic cancer therapy: rationales, targets and drugs

Epigenetic cancer therapy: rationales, targets and drugs

Aberrant DNA methylation of the Src kinase Hck, but not of Lyn, in Philadelphia chromosome negative acute lymphocytic leukemia

Epigenetic regulation of signal transducer and activator of transcription 3 in acute myeloid leukemia

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