Extended experience with a non‐cytotoxic DNMT1‐targeting regimen of decitabine to treat myeloid malignancies
| Autor: | Alan E. Lichtin, Hetty E. Carraway, Ashwin Kishtagari, Yogen Saunthararajah, Jibran Durrani, Tomas Radivoyevitch, Cassandra M Kerr, Bhumika J. Patel, Valeria Visconte, Hassan Awada, Reda Z. Mahfouz, Teodora Kuzmanovic, Jaroslaw P. Maciejewski |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
Antimetabolites Antineoplastic Myeloid DNA damage Short Report Decitabine 03 medical and health sciences 0302 clinical medicine Short Reports Humans Cytotoxic T cell Medicine noncytotoxic DNMT1 depletion Cytotoxicity Aged Aged 80 and over Myeloproliferative Disorders Nucleoside analogue business.industry Hematology myeloid neoplasms Haematological Malignancy – Clinical Regimen medicine.anatomical_structure 030220 oncology & carcinogenesis DNMT1 Cancer research Female business 030215 immunology medicine.drug |
| Zdroj: | British Journal of Haematology |
| ISSN: | 1365-2141 0007-1048 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text