19874311

pubmed:Citation

2

Romidepsin has shown promise in the treatment of T-cell lymphomas, and so we evaluated molecular endpoints gathered from 61 patients enrolled on a phase II trial of romidepsin in cutaneous and peripheral T-cell lymphoma at the National Institutes of Health. The endpoints included histone H3 acetylation and ABCB1 gene expression in peripheral blood mononuclear cells (PBMCs); ABCB1 gene expression in tumour biopsy samples; and blood fetal haemoglobin levels (HbF), all of which were increased following romidepsin treatment. The fold increase in histone acetylation in PBMCs at 24 h was weakly to moderately well correlated with the pharmacokinetic parameters C(max) and area under the curve (AUC)(last) (rho = 0.37, P = 0.03 and rho = 0.36, P = 0.03 respectively) and inversely associated with clearance (rho = -0.44; P = 0.03). Histone acetylation in PBMCs at 24 h was associated with response (P = 0.026) as was the increase in fetal haemoglobin (P = 0.014); this latter association may be due to the longer on-study duration for patients with disease response. Together, these results suggest that pharmacokinetics may be an important determinant of response to histone deacetylase inhibitors (HDIs) - the association with histone acetylation in PBMCs at 24 h is consistent with a hypothesis that potent HDIs are needed for a critical threshold of drug exposure and durable activity.

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http://linkedlifedata.com/resource/pubmed/journal/0372544

http://linkedlifedata.com/resource/pubmed/chemical/ABCB1 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Antibiotics, Antineoplastic, http://linkedlifedata.com/resource/pubmed/chemical/Depsipeptides, http://linkedlifedata.com/resource/pubmed/chemical/Fetal Hemoglobin, http://linkedlifedata.com/resource/pubmed/chemical/Histone Deacetylase Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Histones, http://linkedlifedata.com/resource/pubmed/chemical/P-Glycoprotein, http://linkedlifedata.com/resource/pubmed/chemical/romidepsin

Jan

pubmed-author:BatesSusan ESE, pubmed-author:FiggWilliam DWD, pubmed-author:FojoTitoT, pubmed-author:FryeRobinR, pubmed-author:GardnerErin RER, pubmed-author:LingAlexA, pubmed-author:LuchenkoVictoriaV, pubmed-author:ObrzutTomaszT, pubmed-author:PiekarzRichard LRL, pubmed-author:RobeyRobert WRW, pubmed-author:SteadmanKennethK, pubmed-author:SteinbergSeth MSM, pubmed-author:ToKin WahKW, pubmed-author:TurnerMariaM, pubmed-author:ZhanZhirongZ

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2011-9-29