Phase I Study of Depsipeptide in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Report

Fouladi, Maryam; Furman, Wayne L.; Chin, Thomas K.; Freeman, Burgess B.; Dudkin, Lorina; Stewart, Clinton F.; Krailo, Mark; Speights, Roseanne; Ingle, Ashish M.; Houghton, Peter J.; Wright, John J.; Adamson, Peter C.; Blaney, Susan M.

doi:10.1200/jco.2006.06.4964

Cited by 79 publications

(54 citation statements)

References 30 publications

(5 reference statements)

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“…As shown in Table 3 results), romidepsin significantly increased the surface expression of CD20 on Burkitt lymphoma and B104 cells at 5-10 nM, which were far lower than the maximum plasma concentration determined in phase I clinical trials (1.0-1.4 mM). [36][37][38] Romidepsin also had remarkable cytotoxic activities at the same concentrations (Supplementary Figure S2 and Table S2), consistent with the notion that this drug is one of the most effective HDAC inhibitors against hematological malignancies both in vitro and in vivo. 39,40 The upregulation of CD20 was not generalized to other B-cell-specific antigens, as the expression levels of CD10, CD21, CD43 and CD44 did not change in response to HDAC inhibitors (data not shown).…”

Section: Hdac Inhibitors Enhance the Expression Of Cd20 Antigen On B-supporting

confidence: 66%

“…16,40 However, recent clinical trials concluded that HDAC inhibitors had only limited clinical activity when used as monotherapy. 33,34,[36][37][38] Our present study suggests a more effective way of their application; the ability of HDAC inhibitors to modify the expression of surface molecules may provide a new avenue for the clinical application of HDAC inhibitors, for example, as immunopotentiators or chemosensitizers. Hence, the combination with HDAC inhibitors not only enhances anti-lymphoma activity, but also expands the clinical utility of rituximab for other disorders, such as autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

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HDAC inhibitors augment cytotoxic activity of rituximab by upregulating CD20 expression on lymphoma cells

et al. 2010

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Anti-CD20 antibody rituximab is now essential for the treatment of CD20-positive B-cell lymphomas. Decreased expression of CD20 is one of the major mechanisms underlying both innate and acquired resistance to rituximab. In this study, we show that histone deacetylase (HDAC) inhibitors augment the cytotoxic activity of rituximab by enhancing the surface expression of CD20 antigen on lymphoma cells. HDAC inhibitors, valproic acid (VPA) and romidepsin, increased CD20 expression at protein and mRNA levels in B-cell lymphoma cell lines with relatively low CD20 expression levels. The VPA-mediated increase in CD20 expression occurred at 1 mM, which is clinically achievable and safe, but insufficient for inducing cell death. Chromatin immunoprecipitation assays revealed that HDAC inhibitors transactivated the CD20 gene through promoter hyperacetylation and Sp1 recruitment. HDAC inhibitors potentiated the activity of rituximab in complementdependent cytotoxic assays. In mouse lymphoma models, HDAC inhibitors enhanced CD20 expression along with histone hyperacetylation in transplanted cells, and acted synergistically with rituximab to retard their growth. The combination with HDAC inhibitors may serve as an effective strategy to overcome rituximab resistance in B-cell lymphomas.

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Section: Hdac Inhibitors Enhance the Expression Of Cd20 Antigen On B-supporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

HDAC inhibitors augment cytotoxic activity of rituximab by upregulating CD20 expression on lymphoma cells

et al. 2010

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“…The disposition of romidepsin has been shown to follow a polyexponential decline with a linear elimination and has been described by a 2-compartment pharmacokinetic (PK) model. No apparent nonlinearity has been reported for romidepsin disposition within the range of 1 to 24.9 mg/m 2 (7,8) The PK of romidepsin does not seem to be affected by repeated dosing. The most extensive clinical PK analysis was done recently by Woo and colleagues (9), in which 98 patients were enrolled in a phase II.…”

Section: Romidepsin Metabolism and Pharmacokineticsmentioning

confidence: 99%

“…There have been multiple phase I trials with romidepsin in patients with refractory solid tumors (7,8), chronic leukemia, myeloma (10), acute myeloid leukemia (11), and T-cell lymphoma. The maximum-tolerated dose was established at 17 to 18 mg/m 2 infused over 4 hours on day 1 and day 5 of a 21-day cycle and 13.3 mg on days 1, 8, and 15 of a 28-day cycle.…”

Section: Early Clinical Studies Of Romidepsinmentioning

confidence: 99%

Romidepsin for Cutaneous T-cell Lymphoma

Prince

Dickinson

2012

Clinical Cancer Research

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Cutaneous T-cell lymphomas (CTCL) are relatively rare lymphomas with an annual incidence of approximately 0.2 to 0.8/100,000 and comprise a variety of clinical entities; mycosis fungoides or its leukemic variant Sezary syndrome account for the majority of cases. Advanced-stage disease is typically treated with bexarotene (a retinoid), interferon, or conventional chemotherapeutic agents, but relapses are inevitable. Histone deacetylase inhibitors, which modify the epigenome, are an attractive addition to the armamentarium. On the basis of 2 large phase II studies, the U.S. Food and Drug Administration approved intravenous romidepsin for patients with relapsed and/or refractory CTCL. Romidepsin provides a subset of patients with an opportunity for prolonged clinical responses with a tolerable side effect profile. Clin Cancer Res; 18(13); 3509-15. Ó2012 AACR. The Histone Deacetylase InhibitorsThe histone deacetylase (HDAC) inhibitors target not only the epigenome via histone modification, but also numerous nucleic and cytoplasmic nonhistone proteins. They are powerful and selective inducers of cancer cell apoptosis and modifiers of the tumor microenvironment, as reviewed recently by Dickinson and colleagues (1) and depicted in Fig. 1. HDACs are one target for HDAC inhibitors and can be grouped according to their structure and homology to yeast enzymes and share a common mechanism of action in binding a zinc ion critical to HDAC function.The simplest method of grouping HDAC inhibitors is based on specificity. Class I-specific HDAC inhibitors include benzamide derivatives (entinostat, mocetinostat) and cyclic tetrapeptides. Romidepsin, isolated from Chromobacterium violaceum (previously called depsipeptide, FK228, FR901228) is one such bicyclic peptide (1). The pan-HDAC inhibitors include the hydroxamic acid derivatives [trichostatin A, vorinostat (suberoylanilide hydroxamic acid), and panobinostat (LBH589)]. They were thought to inhibit all of the zinc-dependent HDACs; however, recent data suggest a relatively reduced effect of the hydoxamates on class IIa enzymes (HDACs 4, 5, 7, and 9; ref. 2). A key difference between the pan-HDAC inhibitors and the class I-specific HDAC inhibitors is thought to be the inhibition of cytoplasmic HDAC6. It is important to note here that, currently, very little suggests that this potential mechanistic difference between the pan-HDAC inhibitors and the isotype-selective HDAC inhibitors, such as romidepsin, affects the response rates [in cutaneous T-cell lymphoma (CTCL), at least]. Response rates to the pan-HDAC inhibitor vorinostat in CTCL are similar to those of romidepsin; however, there may be a difference in toxicity profiles. Preliminary Studies of RomidepsinRomidepsin induces apoptosis in many human tumor cell lines and in various xenograft models (3-5). The most comprehensive preclinical studies of romidepsin in a CTCL model have been done by Piekarz and colleagues (6). These investigators used the human T-cell lymphoma cell line HUT78 to test for sensitivity and molecu...

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“…23 A preclinical study in rats showed that 66% of the dose was excreted into the bile, mediated via the ATP-binding cassette transporter ABCB 1(P-glycoprotein, MDR1), for which romidepsin has been identified as a substrate. 24 Romidepsin is also likely to be a substrate of the organic transporter, OATP1B3, an influx transporter encoded by SLCO1B3, because other cyclic peptides have been shown to interact with the same transporter.…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 99%

Peripheral T cell lymphoma: clinical utility of romidepsin

Zain¹,

Sawey²

2012

BLCTT

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Introduction: Direct therapeutic targets, such as aberrant tumor cell genes and tumor cell markers, have been the focus of cancer treatment for more than 50 years. The resulting damage to normal cells and emergence of drug-resistant tumor cells after exposure to conventional chemotherapy have led researchers to study indirect targets, like the tumor vasculature. A more recent indirect approach involves targeting the epigenetic modifiers, DNA methyltransferase and histone deacetylase. Histone deacetylase inhibitors have been shown to be active cytotoxic agents in T cell lymphoma. The current treatments approved by the US Food and Drug Administration for relapsed cutaneous T cell lymphoma are vorinostat and romidepsin. The diversity and rarity of peripheral T cell lymphomas present a challenge for effective treatment. With their poor overall survival rate, new targeted therapies need to be developed.

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Phase I Study of Depsipeptide in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Report

Cited by 79 publications

References 30 publications

HDAC inhibitors augment cytotoxic activity of rituximab by upregulating CD20 expression on lymphoma cells

HDAC inhibitors augment cytotoxic activity of rituximab by upregulating CD20 expression on lymphoma cells

Romidepsin for Cutaneous T-cell Lymphoma

Peripheral T cell lymphoma: clinical utility of romidepsin

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