期刊
BRITISH JOURNAL OF HAEMATOLOGY
卷 148, 期 2, 页码 256-267出版社
WILEY
DOI: 10.1111/j.1365-2141.2009.07954.x
关键词
histone deacetylase inhibitor; romidepsin; p-glycoprotein; fetal haemoglobin; T-cell lymphoma
类别
资金
- National Cancer Institute
- National Institutes of Health [N01-CO-12400]
- Center for Cancer Research
- NATIONAL CANCER INSTITUTE [ZICSC006537, ZIABC010621, ZIDSC007202, ZICBC010548, ZICSC006536] Funding Source: NIH RePORTER
P>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 center dot 37, P = 0 center dot 03 and rho = 0 center dot 36, P = 0 center dot 03 respectively) and inversely associated with clearance (rho = -0 center dot 44; P = 0 center dot 03). Histone acetylation in PBMCs at 24 h was associated with response (P = 0 center dot 026) as was the increase in fetal haemoglobin (P = 0 center dot 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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