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Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy
PURPOSE: When integrating molecularly targeted compounds in radiotherapy, synergistic effects of the systemic agent and radiation may extend the limits of patient tolerance, increasing the demand for understanding the pathophysiological mechanisms of treatment toxicity. In this Pelvic Radiation and...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Korean Cancer Association
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398387/ https://www.ncbi.nlm.nih.gov/pubmed/27488871 http://dx.doi.org/10.4143/crt.2016.080 |
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author | Kalanxhi, Erta Risberg, Karianne Barua, Imon S. Dueland, Svein Waagene, Stein Andersen, Solveig Norheim Pettersen, Solveig J. Lindvall, Jessica M. Redalen, Kathrine Røe Flatmark, Kjersti Ree, Anne Hansen |
author_facet | Kalanxhi, Erta Risberg, Karianne Barua, Imon S. Dueland, Svein Waagene, Stein Andersen, Solveig Norheim Pettersen, Solveig J. Lindvall, Jessica M. Redalen, Kathrine Røe Flatmark, Kjersti Ree, Anne Hansen |
author_sort | Kalanxhi, Erta |
collection | PubMed |
description | PURPOSE: When integrating molecularly targeted compounds in radiotherapy, synergistic effects of the systemic agent and radiation may extend the limits of patient tolerance, increasing the demand for understanding the pathophysiological mechanisms of treatment toxicity. In this Pelvic Radiation and Vorinostat (PRAVO) study, we investigated mechanisms of adverse effects in response to the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) when administered as a potential radiosensitiser. MATERIALS AND METHODS: This phase I study for advanced gastrointestinal carcinoma was conducted in sequential patient cohorts exposed to escalating doses of vorinostat combined with standard-fractionated palliative radiotherapy to pelvic target volumes. Gene expression microarray analysis of the study patient peripheral blood mononuclear cells (PBMC) was followed by functional validation in cultured cell lines and mice treated with SAHA. RESULTS: PBMC transcriptional responses to vorinostat, including induction of apoptosis, were confined to the patient cohort reporting dose-limiting intestinal toxicities. At relevant SAHA concentrations, apoptotic features (annexin V staining and caspase 3/7 activation, but not poly-(ADP-ribose)-polymerase cleavage) were observed in cultured intestinal epithelial cells. Moreover, SAHA-treated mice displayed significant weight loss. CONCLUSION: The PRAVO study design implemented a strategy to explore treatment toxicity caused by an HDAC inhibitor when combined with radiotherapy and enabled the identification of apoptosis as a potential mechanism responsible for the dose-limiting effects of vorinostat. To the best of our knowledge, this is the first report deciphering mechanisms of normal tissue adverse effects in response to an HDAC inhibitor within a combined-modality treatment regimen. |
format | Online Article Text |
id | pubmed-5398387 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Korean Cancer Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-53983872017-05-05 Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy Kalanxhi, Erta Risberg, Karianne Barua, Imon S. Dueland, Svein Waagene, Stein Andersen, Solveig Norheim Pettersen, Solveig J. Lindvall, Jessica M. Redalen, Kathrine Røe Flatmark, Kjersti Ree, Anne Hansen Cancer Res Treat Original Article PURPOSE: When integrating molecularly targeted compounds in radiotherapy, synergistic effects of the systemic agent and radiation may extend the limits of patient tolerance, increasing the demand for understanding the pathophysiological mechanisms of treatment toxicity. In this Pelvic Radiation and Vorinostat (PRAVO) study, we investigated mechanisms of adverse effects in response to the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) when administered as a potential radiosensitiser. MATERIALS AND METHODS: This phase I study for advanced gastrointestinal carcinoma was conducted in sequential patient cohorts exposed to escalating doses of vorinostat combined with standard-fractionated palliative radiotherapy to pelvic target volumes. Gene expression microarray analysis of the study patient peripheral blood mononuclear cells (PBMC) was followed by functional validation in cultured cell lines and mice treated with SAHA. RESULTS: PBMC transcriptional responses to vorinostat, including induction of apoptosis, were confined to the patient cohort reporting dose-limiting intestinal toxicities. At relevant SAHA concentrations, apoptotic features (annexin V staining and caspase 3/7 activation, but not poly-(ADP-ribose)-polymerase cleavage) were observed in cultured intestinal epithelial cells. Moreover, SAHA-treated mice displayed significant weight loss. CONCLUSION: The PRAVO study design implemented a strategy to explore treatment toxicity caused by an HDAC inhibitor when combined with radiotherapy and enabled the identification of apoptosis as a potential mechanism responsible for the dose-limiting effects of vorinostat. To the best of our knowledge, this is the first report deciphering mechanisms of normal tissue adverse effects in response to an HDAC inhibitor within a combined-modality treatment regimen. Korean Cancer Association 2017-04 2016-07-28 /pmc/articles/PMC5398387/ /pubmed/27488871 http://dx.doi.org/10.4143/crt.2016.080 Text en Copyright © 2016 by the Korean Cancer Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Kalanxhi, Erta Risberg, Karianne Barua, Imon S. Dueland, Svein Waagene, Stein Andersen, Solveig Norheim Pettersen, Solveig J. Lindvall, Jessica M. Redalen, Kathrine Røe Flatmark, Kjersti Ree, Anne Hansen Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy |
title | Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy |
title_full | Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy |
title_fullStr | Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy |
title_full_unstemmed | Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy |
title_short | Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy |
title_sort | induction of apoptosis in intestinal toxicity to a histone deacetylase inhibitor in a phase i study with pelvic radiotherapy |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398387/ https://www.ncbi.nlm.nih.gov/pubmed/27488871 http://dx.doi.org/10.4143/crt.2016.080 |
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