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Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker.

ABSTRACT: Histone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase inhibitors by increasing their access and binding to DNA.This phase I trial was designed to determine the toxicity profile, tolerability, and recommended phase II dose of escalating doses of the HDACi vorinostat, with weekly doxorubicin.In total, 32 patients were treated; vorinostat was dosed at 400, 600, 800, or 1000 mg day(-1) on days 1-3, followed by doxorubicin (20 mg m(-2)) on day 3 for 3 of 4 weeks. Maximal tolerated dose was determined to be 800 mg day(-1) of vorinostat. Dose-limiting toxicities were grade 3 nausea/vomiting (two out of six) and fatigue (one out of six) at 1000 mg day(-1). Non-dose-limiting grade 3/4 toxicities included haematological toxicity and venous thromboembolism. Antitumor activity in 24 evaluable patients included two partial responses (breast and prostate cancer). Two patients with melanoma had stable disease for > or =8 months. Histone hyperacetylation changes in peripheral blood mononuclear and tumour cells were comparable. Histone hyperacetylation seemed to correlate with pre-treatment HDAC2 expression.These findings suggest that vorinostat can be combined with weekly doxorubicin in this schedule at a dose of 800 mg day(-1). The HDAC2 expression may be a marker predictive of HDAC inhibition. Antitumor activity of this regimen in breast cancer, prostate cancer, and melanoma seems interesting.

SUBMITTER: Munster PN

PROVIDER: S-EPMC2768109 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker.

Munster P N PN Marchion D D Thomas S S Egorin M M Minton S S Springett G G Lee J-H JH Simon G G Chiappori A A Sullivan D D Daud A A

British journal of cancer 20090908 7

<h4>Background</h4>Histone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase inhibitors by increasing their access and binding to DNA.<h4>Methods</h4>This phase I trial was designed to determine the toxicity profile, tolerability, and recommended phase II dose of escalating doses of the HDACi vorinostat, with weekly doxorubicin.<h4>Results</h4>In total, 32 patients were treated; vorinostat was dosed at 400, 600, 800, or 1000 mg day(-1) on days 1-3, followed by doxorubici ...[more]

PMID: 19738609

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Project description:Canine urothelial carcinoma (cUC) is the most common tumor of the lower urinary tract in dogs. Although chemotherapy and radical surgery have improved the overall survival, most dogs with cUC succumb to metastasis or recurrence. Therefore, the development of an effective systematic therapy is warranted. In this study, a comprehensive drug screening test using a cUC cell line was performed and the anti-tumor effect of a histone deacetylase (HDAC) inhibitor was evaluated. Comprehensive drug screening was performed on cUC cells. Based on this screening, the anti-proliferation effect of vorinostat, an HDAC inhibitor clinically applied in humans, was evaluated using several cUC cell lines in sulforhodamine B and flow cytometry assays. Western blot analysis was also performed to evaluate the degree of acetylation of histone H3 as well as the expression and phosphorylation of cell cycle-related molecules. The anti-tumor effect of vorinostat in vivo was evaluated using a xenograft model. Finally, immunohistochemistry was performed on acetyl-histone H3 in cUC and the relationship between the degree of acetylation and prognosis was examined using Kaplan-Meier survival analysis. Drug screening revealed that HDAC inhibitors consistently inhibited the growth of cUC cells. Vorinostat inhibited the growth of 6 cUC cell lines in a dose-dependent manner and induced G0/G1 cell cycle arrest. Western blot analysis showed that vorinostat mediated the acetylation of histone H3, the dephosphorylation of p-Rb, and the upregulation of p21 upon exposure to vorinostat. Furthermore, inhibition of tumor growth was observed in the xenograft model. In clinical cUC cases, neoplastic urothelium showed significant deacetylation of histones compared to the normal control, where lower histone acetylation levels were associated with a poor prognosis. In conclusion, the therapeutic potential of vorinostat was demonstrated in cUC. Histone deacetylation may be related to cUC tumor progression.

Dataset Information

Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker.

Publications

Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker.

Similar Datasets

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