Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome Journal Article

  

Authors:	Maslak, P.; Chanel, S.; Camacho, L. H.; Soignet, S.; Pandolfi, P. P.; Guernah, I.; Warrell, R.; Nimer, S.
Article Title:	Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome
Abstract:	Epigenetic mechanisms underlying tumorigenesis have recently received much attention as potential therapeutic targets of human cancer. We designed a pilot study to target DNA methylation and histone deacetylation through the sequential administration of 5-azacytidine followed by sodium phenylbutyrate (PB) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Ten evaluable patients (eight AML, two MDS) were treated with seven consecutive daily subcutaneous injections of 5-azacytidine at 75mg/m2 followed by 5 days of sodium PB given intravenously at a dose of 200mg/kg. Five patients (50%) were able to achieve a beneficial clinical response (partial remission or stable disease). One patient with MDS proceeded to allogeneic stem cell transplantation and is alive without evidence of disease 39 months later. The combination regimen was well tolerated with common toxicities of injection site skin reaction (90% of the patients) from 5-azacytidine, and somnolence/fatigue from the sodium PB infusion (80% of the patients). Correlative laboratory studies demonstrated the consistent reacetylation of histone H4, although no relationship with the clinical response could be demonstrated. Results from this pilot study demonstrate that a combination approach targeting different mechanisms of transcriptional modulation is clinically feasible with acceptable toxicity and measurable biologic and clinical outcomes. © 2006 Nature Publishing Group. All rights reserved.
Keywords:	adult; clinical article; controlled study; treatment outcome; aged; middle aged; acute granulocytic leukemia; human cell; allogeneic stem cell transplantation; clinical trial; drug tolerability; fatigue; diarrhea; drug safety; antineoplastic agents; drug targeting; skin manifestation; cytarabine; controlled clinical trial; antimetabolites, antineoplastic; nausea; vomiting; drug administration schedule; transcription, genetic; antineoplastic activity; dna methylation; dizziness; febrile neutropenia; injection site reaction; arsenic trioxide; drug fatality; correlation analysis; antiinfective agent; myelodysplastic syndrome; transcription regulation; drug therapy, combination; pilot study; pilot projects; epigenetics; leukemia, myeloid; drug response; targeted therapy; idarubicin; somnolence; histones; retinoic acid; brain hemorrhage; azacitidine; myelodysplastic syndromes; deacetylation; acute disease; acetylation; electrolyte disturbance; leukemia remission; histone h4; disorientation; 4 phenylbutyric acid; acute myeloid leukemia; phenylbutyrates; hhistone deacetylation
Journal Title:	Leukemia
Volume:	20
Issue:	2
ISSN:	0887-6924
Publisher:	Nature Publishing Group
Date Published:	2006-02-01
Start Page:	212
End Page:	217
Language:	English
DOI:	10.1038/sj.leu.2404050
PUBMED:	16357841
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-31444438952&partnerID=40&md5=6c575772e0fd7e280705e8ebb2e531ee
Notes:	--- - "Cited By (since 1996): 57" - "Export Date: 4 June 2012" - "CODEN: LEUKE" - "Source: Scopus"

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