Evaluation of safety, pharmacokinetics, and efficacy of vorinostat, a histone deacetylase inhibitor, in the treatment of gastrointestinal (GI) cancer in a phase I clinical trial

Doi, Toshihiko; Hamaguchi, Tetsuya; Shirao, Kuniaki; Chin, Keisho; Hatake, Kiyohiko; Noguchi, Kazuo; Otsuki, Tetsuya; Mehta, Anish; Ohtsu, Atsushi

doi:10.1007/s10147-011-0348-6

Cited by 33 publications

(15 citation statements)

References 28 publications

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“…Currently, HDAC inhibitors are used in the clinical setting as anti-cancer (vorinostat, an inhibitor of HDAC1, 2, 3, and 6) or psychotropic (VPA, an inhibitor of HDAC1, 2, 3, and 8) drugs. Interestingly, cancer patients treated with HDAC inhibitors develop hyperglycemia as a side effect [ 47 , 48 ], suggesting that HDAC inhibition may reduce insulin signaling in some organs. Our results provide a mechanism by which HDAC inhibition may impair glucose tolerance.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase regulates insulin signaling via two pathways in pancreatic β cells

et al. 2017

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Recent studies demonstrated that insulin signaling plays important roles in the regulation of pancreatic β cell mass, the reduction of which is known to be involved in the development of diabetes. However, the mechanism underlying the alteration of insulin signaling in pancreatic β cells remains unclear. The involvement of epigenetic control in the onset of diabetes has also been reported. Thus, we analyzed the epigenetic control of insulin receptor substrate 2 (IRS2) expression in the MIN6 mouse insulinoma cell line. We found concomitant IRS2 up-regulation and enhanced insulin signaling in MIN6 cells, which resulted in an increase in cell proliferation. The H3K9 acetylation status of the Irs2 promoter was positively associated with IRS2 expression. Treatment of MIN6 cells with histone deacetylase inhibitors led to increased IRS2 expression, but this occurred in concert with low insulin signaling. We observed increased IRS2 lysine acetylation as a consequence of histone deacetylase inhibition, a modification that was coupled with a decrease in IRS2 tyrosine phosphorylation. These results suggest that insulin signaling in pancreatic β cells is regulated by histone deacetylases through two novel pathways affecting IRS2: the epigenetic control of IRS2 expression by H3K9 promoter acetylation, and the regulation of IRS2 activity through protein modification. The identification of the histone deacetylase isoform(s) involved in these mechanisms would be a valuable approach for the treatment of type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Histone deacetylase regulates insulin signaling via two pathways in pancreatic β cells

et al. 2017

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“…However, it has been estimated at 43% in one report of patients with advanced cancer (Kelly et al ., ). Most human studies report a C max of 1–1.5 μ m at similar dosages to those used here on a body surface area basis (400 mg/day or ~250 mg/m 2 ; Rubin et al ., ; Ramalingam et al ., ; Doi et al ., ). Surprisingly, the half‐life of SAHA in cats following i.v.…”

Section: Calculated Mean ± Standard Deviation Noncompartmental Pharmamentioning

confidence: 97%

Pharmacokinetics and pharmacodynamics of suberoylanilide hydroxamic acid in cats

McDonnel

Tell

Murphy

2013

Vet Pharm & Therapeutics

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Suberoylanilidehydroxamic acid (SAHA), or vorinostat, is a histone deacetylase inhibitor approved for use as chemotherapy for lymphoma in humans. The goal of this study was to establish pharmacological parameters of SAHA in cats. Our interest in treating cats with SAHA is two-fold: as an anti-cancer chemotherapeutic and as anti-latency therapy for feline retroviral infections. Relying solely on data from studies in other animals would be inappropriate as SAHA is partially metabolized by glucuronidation, which is absent in feline metabolism. SAHA was administered to cats intravenously (2 mg/kg) or orally (250 mg/m2, ~17 mg/kg) in a cross-over study design. Clinically, SAHA was well tolerated at these dosages as no abnormalities were noted following administration. The pharmacokinetics of SAHA in cats was found to be similar to that of dogs, but the overall serum drug exposure was much less than that of humans at an equivalent dose. The pharmacodynamic effect of an increase in acetylated histone proteins in blood was detected after both routes of administration. An increased oral dose of 60 mg SAHA/kg administered to one animal resulted in a surprisingly modest increase in peak drug concentration, suggesting possible saturation of absorption kinetics. This study provides a foundation for future studies of the clinical efficacy of SAHA in treating feline disease.

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“…Currently vorinostat in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) that exhibits poor prognosis by itself is in clinical trials for treating patients with untreated PTCL [ 43 ]. Vorinostat has also been found to be a potent agent in the treatment of gastrointestinal (GI) cancer [ 44 ]. Vorinostat has also been implicated in having an effect on other types of cancers, such as brain metastasis, refractory colorectal, advanced solid tumors, melanoma, pancreatic, lung cancer and multiple myeloma.…”

Section: Fda Approved Drugsmentioning

confidence: 99%

Histone Deacetylase Inhibitors in Clinical Studies as Templates for New Anticancer Agents

et al. 2015

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Histone dacetylases (HDACs) are a group of enzymes that remove acetyl groups from histones and regulate expression of tumor suppressor genes. They are implicated in many human diseases, especially cancer, making them a promising therapeutic target for treatment of the latter by developing a wide variety of inhibitors. HDAC inhibitors interfere with HDAC activity and regulate biological events, such as cell cycle, differentiation and apoptosis in cancer cells. As a result, HDAC inhibitor-based therapies have gained much attention for cancer treatment. To date, the FDA has approved three HDAC inhibitors for cutaneous/peripheral T-cell lymphoma and many more HDAC inhibitors are in different stages of clinical development for the treatment of hematological malignancies as well as solid tumors. In the intensifying efforts to discover new, hopefully more therapeutically efficacious HDAC inhibitors, molecular modeling-based rational drug design has played an important role in identifying potential inhibitors that vary in molecular structures and properties. In this review, we summarize four major structural classes of HDAC inhibitors that are in clinical trials and different computer modeling tools available for their structural modifications as a guide to discover additional HDAC inhibitors with greater therapeutic utility.

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Evaluation of safety, pharmacokinetics, and efficacy of vorinostat, a histone deacetylase inhibitor, in the treatment of gastrointestinal (GI) cancer in a phase I clinical trial

Cited by 33 publications

References 28 publications

Histone deacetylase regulates insulin signaling via two pathways in pancreatic β cells

Histone deacetylase regulates insulin signaling via two pathways in pancreatic β cells

Pharmacokinetics and pharmacodynamics of suberoylanilide hydroxamic acid in cats

Histone Deacetylase Inhibitors in Clinical Studies as Templates for New Anticancer Agents

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