A liquid chromatography/tandem mass spectrometry assay to quantitate MS-275 in human plasma

Zhao, Ming; Rudek, Michelle A.; Mnasakanyan, Aleksandr; Hartke, Carol; Пили, Роберто; Baker, Sharyn D.

doi:10.1016/j.jpba.2006.08.006

Cited by 16 publications

(12 citation statements)

References 7 publications

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“…The median plasma concentration 30 min following MS-275 (5 mg/kg) administration was 20.6 F 5.01 ng/mL. This pharmacokinetic analysis was done based on previously published methodology (32). Nanomolar peak plasma concentrations of MS-275 were able to induce the observed immunomodulation in the RENCA model.…”

Section: Discussionmentioning

confidence: 99%

Synergistic In vivo Antitumor Effect of the Histone Deacetylase Inhibitor MS-275 in Combination with Interleukin 2 in a Murine Model of Renal Cell Carcinoma

Kato

Yoshimura

Shin³

et al. 2007

Clinical Cancer Research

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Purpose: High-dose interleukin 2 (IL-2) is a Food and Drug Administration^approved regimen for patients with metastatic renal cell carcinoma. However, the toxicity and limited clinical benefit associated with IL-2 has hampered its use. Histone deacetylase (HDAC) inhibitors have been shown to have antitumor activity in different tumor models including renal cell carcinoma, and to have immunomodulatory properties. In our study, we tested the effectiveness of combination therapy of IL-2 with the HDAC inhibitor MS-275 in a murine renal cell carcinoma (RENCA) model. Experimental Design: RENCA luciferase^expressing cells were implanted in the left kidney of BALB/C mice. Animals were randomly divided into four groups and treated with either vehicle, 150,000 IU of IL-2 twice daily by i.p. injections (twice weekly), 5 mg/kg of MS-275 daily by oral gavage (5 d/wk), or its combination.Treatment was started either 3 or 9 days following tumor cell injection. Results: Weekly luciferase images and tumor weight after 2 weeks of treatment showed significant tumor inhibition (>80%) in the combination treatment as compared with the IL-2 (no significant inhibition) or MS-275 (f40% inhibition) treatment groups. Spontaneous lung metastases were also inhibited in the combination treatment (>90% inhibition) as compared with the single treatment group. Kaplan-Meier analyses showed statistically significant increased survival in the combination group as compared with controls and single agents. Splenocytes from mice treated with combination treatment showed greater lysis of RENCA cells than splenocytes from mice treated with single agents. The percentage of CD4 + CD25+ Tcells and Foxp3 + T cells (T regulatory cells) was increased or reduced, respectively, in lymph nodes from tumor-bearing animals treated with the combination of MS-275 and IL-2 as compared with control and single agents. Depletion of CD8 + T cells abrogated the survival benefit from MS-275 + IL-2 combination. Conclusions: These results show that the combination of IL-2 and MS-275 has a synergistic antitumor effect in vivo in an immunocompetent murine model of renal cell carcinoma. The antitumor effect was associated with the decreased number of T regulatory cells and the increased antitumor cytotoxicity by splenocytes. In conclusion, these preclinical data provide the rationale for clinical testing of the combination of IL-2 and HDAC inhibitors in the treatment of patients with renal cell carcinoma.

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Section: Discussionmentioning

confidence: 99%

Synergistic In vivo Antitumor Effect of the Histone Deacetylase Inhibitor MS-275 in Combination with Interleukin 2 in a Murine Model of Renal Cell Carcinoma

Kato

Yoshimura

Shin³

et al. 2007

Clinical Cancer Research

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“…(19, 20) AZA pharmacokinetic parameters were determined as previously described. (21) Entinostat trough concentrations (C min ) were considered reportable if they were collected pre-treatment on day 10.…”

Section: Methodsmentioning

confidence: 99%

Combination Epigenetic Therapy in Advanced Breast Cancer with 5-Azacitidine and Entinostat: A Phase II National Cancer Institute/Stand Up to Cancer Study

Connolly

Jankowitz

et al. 2017

Clinical Cancer Research

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117

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Purpose In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to re-expression of genes encoding important therapeutic targets including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine (AZA) and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC). Patients and Methods Patients received AZA 40 mg/m2 (days 1–5, 8–10) and entinostat 7 mg (days 3,10) of 28 day cycle. Continuation of epigenetic therapy was offered with addition of endocrine therapy at time of progression (optional continuation, OC phase). Primary endpoint was objective response rate (ORR) in each cohort. We hypothesized that ORR would be ≥20% against null of 5% using Simon two-stage design. At least 1 response was required in 1st of 13 patients per cohort to continue accrual to 27 per cohort. Type I error 4%, power 90%. Results There was one partial response among 27 women with hormone-resistant disease (ORR=4%, 95% CI=0–19%), and none in 13 women with TNBC. One additional partial response was observed in the OC phase in the hormone-resistant cohort (n=12). Mandatory tumor samples were obtained pre- and post-treatment (58% paired) with either up- or down-regulation of ER observed in approximately 50% of post-treatment biopsies in the hormone-resistant, but not TNBC cohort. Conclusion Combination epigenetic therapy was well tolerated but our primary endpoint was not met. OC phase results suggest that some women benefit from epigenetic therapy and/or reintroduction of endocrine therapy beyond progression but further study is needed.

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“…Samples were collected on days 1, 8 and 15 of cycle 1 for PK studies using a validated liquid chromatographytandem mass spectrometry (LC-MS/MS) assay performed in the Analytical Pharmacology Core laboratory at the Sidney Kimmel Comprehensive Center at Johns Hopkins Medical Center. 23 Samples were collected at 0 hours (pre-dose), 0.25, 1, and 2 hours post dose as well as pre-dose on days 8 and 15.…”

Section: Correlative Studiesmentioning

confidence: 99%

ENGAGE- 501: phase II study of entinostat (SNDX-275) in relapsed and refractory Hodgkin lymphoma

Batlevi

Kasamon²,

Bociek

et al. 2016

Haematologica

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A liquid chromatography/tandem mass spectrometry assay to quantitate MS-275 in human plasma

Cited by 16 publications

References 7 publications

Synergistic In vivo Antitumor Effect of the Histone Deacetylase Inhibitor MS-275 in Combination with Interleukin 2 in a Murine Model of Renal Cell Carcinoma

Synergistic In vivo Antitumor Effect of the Histone Deacetylase Inhibitor MS-275 in Combination with Interleukin 2 in a Murine Model of Renal Cell Carcinoma

Combination Epigenetic Therapy in Advanced Breast Cancer with 5-Azacitidine and Entinostat: A Phase II National Cancer Institute/Stand Up to Cancer Study

ENGAGE- 501: phase II study of entinostat (SNDX-275) in relapsed and refractory Hodgkin lymphoma

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