TY - JOUR
T1 - Combination therapy with DNA methyltransferase inhibitors in hematologic malignancies
AU - Gore, Steven D.
PY - 2005/12/1
Y1 - 2005/12/1
N2 - A variety of epigenetic changes contribute to transcriptional dysregulation in myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML). DNA methyltransferase (DNMT) inhibitors - azacitidine and decitabine - have significant activity in the treatment of MDS. Despite marked activity in myeloid malignancy, monotherapy with DNMT inhibitors is limited by low complete and partial response rates (7-20%) and median response durations of 15 months. As with classical cytotoxic therapy, the targeting of biologic pathways and mechanisms may best be accomplished using a combination of agents offering complementary mechanisms and synergistic pharmacodynamic interactions. The goal of this approach is to improve response rates, quality, and duration, and to minimize adverse events. There are a number of new therapies under development for the management of MDS and AML. This review article touches on some of the more promising combination regimens in various phases of investigation. The treatment of MDS and AML is undergoing rapid evolution. Cytogenetic complete remission and prolonged survival represent important goals. Incremental improvements in disease state and quality-of-life issues are also important for patients. Given the overall failure of cytotoxic chemotherapy in the achievement of cures in MDS and MDS-related AML, the application of less toxic, biologically directed agents may represent a more promising approach to treatment. Combination therapies with DNMT inhibitors using optimal dosing regimens to focus on methylation reversal with lower doses over longer periods of time, rather than direct cytotoxic effects, are beginning to suggest promising results in MDS and AML.
AB - A variety of epigenetic changes contribute to transcriptional dysregulation in myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML). DNA methyltransferase (DNMT) inhibitors - azacitidine and decitabine - have significant activity in the treatment of MDS. Despite marked activity in myeloid malignancy, monotherapy with DNMT inhibitors is limited by low complete and partial response rates (7-20%) and median response durations of 15 months. As with classical cytotoxic therapy, the targeting of biologic pathways and mechanisms may best be accomplished using a combination of agents offering complementary mechanisms and synergistic pharmacodynamic interactions. The goal of this approach is to improve response rates, quality, and duration, and to minimize adverse events. There are a number of new therapies under development for the management of MDS and AML. This review article touches on some of the more promising combination regimens in various phases of investigation. The treatment of MDS and AML is undergoing rapid evolution. Cytogenetic complete remission and prolonged survival represent important goals. Incremental improvements in disease state and quality-of-life issues are also important for patients. Given the overall failure of cytotoxic chemotherapy in the achievement of cures in MDS and MDS-related AML, the application of less toxic, biologically directed agents may represent a more promising approach to treatment. Combination therapies with DNMT inhibitors using optimal dosing regimens to focus on methylation reversal with lower doses over longer periods of time, rather than direct cytotoxic effects, are beginning to suggest promising results in MDS and AML.
KW - Acute myeloid leukemia
KW - Azacitidine
KW - DNA methyltransferase inhibitors
KW - Decitabine
KW - Myelodysplastic syndrome
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U2 - 10.1038/ncponc0346
DO - 10.1038/ncponc0346
M3 - Review article
C2 - 16341238
AN - SCOPUS:31344446955
SN - 1743-4254
VL - 2
SP - S30-S35
JO - Nature Clinical Practice Oncology
JF - Nature Clinical Practice Oncology
IS - SUPPL. 1
ER -