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Extended experience with a non-cytotoxic DNMT1-targeting regimen of decitabine to treat myeloid malignancies.

ABSTRACT: The nucleoside analogue decitabine can deplete the epigenetic regulator DNA methyltransferase 1 (DNMT1), an effect that occurs, and is saturated at, low concentrations/doses. A reason to pursue this molecular-targeted effect instead of the DNA damage/cytotoxicity produced with high concentrations/doses, is that non-cytotoxic DNMT1-depletion can cytoreduce even p53-null myeloid malignancies while sparing normal haematopoiesis. We thus identified minimum doses of decitabine (0·1-0·2 mg/kg) that deplete DNMT1 without off-target anti-metabolite effects/cytotoxicity, and then administered these well-tolerated doses frequently 1-2X/week to increase S-phase dependent DNMT1-depletion, and used a Myeloid Malignancy Registry to evaluate long-term outcomes in 69 patients treated this way. Consistent with the scientific rationale, treatment was well-tolerated and durable responses were produced (~40%) in genetically heterogeneous disease and the very elderly.

SUBMITTER: Awada H

PROVIDER: S-EPMC7154732 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Extended experience with a non-cytotoxic DNMT1-targeting regimen of decitabine to treat myeloid malignancies.

Awada Hassan H Mahfouz Reda Z RZ Kishtagari Ashwin A Kuzmanovic Teodora T Durrani Jibran J Kerr Cassandra M CM Patel Bhumika J BJ Visconte Valeria V Radivoyevitch Tomas T Lichtin Alan A Carraway Hetty E HE Maciejewski Jaroslaw P JP Saunthararajah Yogen Y

British journal of haematology 20191117 6

The nucleoside analogue decitabine can deplete the epigenetic regulator DNA methyltransferase 1 (DNMT1), an effect that occurs, and is saturated at, low concentrations/doses. A reason to pursue this molecular-targeted effect instead of the DNA damage/cytotoxicity produced with high concentrations/doses, is that non-cytotoxic DNMT1-depletion can cytoreduce even p53-null myeloid malignancies while sparing normal haematopoiesis. We thus identified minimum doses of decitabine (0·1-0·2 mg/kg) that de ...[more]

PMID: 31736067

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Dataset Information

Extended experience with a non-cytotoxic DNMT1-targeting regimen of decitabine to treat myeloid malignancies.

Publications

Extended experience with a non-cytotoxic DNMT1-targeting regimen of decitabine to treat myeloid malignancies.

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