Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy.
- Author:
Erta KALANXHI
1
;
Karianne RISBERG
;
Imon S BARUA
;
Svein DUELAND
;
Stein WAAGENE
;
Solveig Norheim ANDERSEN
;
Solveig J PETTERSEN
;
Jessica M LINDVALL
;
Kathrine Røe REDALEN
;
Kjersti FLATMARK
;
Anne Hansen REE
Author Information
- Publication Type:Original Article
- Keywords: Histone deacetylase inhibitors; Drug-related side effects and adverse reactions; Apoptosis; Radiotherapy; Phase I Clinical Trials
- MeSH: Animals; Apoptosis*; Cells, Cultured; Clinical Trials, Phase I as Topic; Cohort Studies; Drug-Related Side Effects and Adverse Reactions; Epithelial Cells; Gene Expression; Histone Deacetylase Inhibitors*; Histone Deacetylases*; Histones*; Humans; Hydroxamic Acids; Mice; Microarray Analysis; Radiotherapy*; Weight Loss
- From:Cancer Research and Treatment 2017;49(2):374-386
- CountryRepublic of Korea
- Language:English
- Abstract: 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.
