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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.

The increased expression of markers associated with a differentiated phenotype, such as P-glycoprotein (Pgp), follows treatment with histone deacetylase inhibitors. Because depsipeptide (FR901228, FK228, NSC630176) is a substrate for Pgp, up-regulation of the gene that encodes it, MDR1, would mean that depsipeptide induces its own mechanism of resistance. To examine the effect of depsipeptide on expression of ATP-binding cassette transporters associated with multidrug resistance, the kidney cancer cell lines 108, 121, 127, and 143 were treated with depsipeptide and evaluated by quantitative reverse transcription-PCR. Increased levels of MDR1 (1.3- to 6.3-fold) and ABCG2 (3.2- to 11.1-fold) but not MRP1 (0.9- to 1.3-fold) were observed. The induced Pgp transported the fluorescent substrates rhodamine 123, bisantrene, calcein-AM, BODIPY-vinblastine, and BODIPY-paclitaxel. In normal peripheral blood mononuclear cells (PBMC) and circulating tumor cells obtained from patients receiving depsipeptide, increased levels of histone H3 acetylation were found. We next examined MDR1 levels in normal and malignant PBMCs obtained from 15 patients enrolled in clinical trials with depsipeptide and detected up to a 6-fold increase in normal PBMCs and up to an 8-fold increase in circulating tumor cells after depsipeptide administration. In one patient with Sézary syndrome, increased MDR1 gene expression was accompanied by increased cell surface Pgp expression in circulating Sézary cells as determined by measurement of MRK-16 staining by flow cytometry. These studies suggest that depsipeptide induces its own mechanism of resistance and thus provide a basis for clinical trials evaluating depsipeptide in combination with a Pgp inhibitor.