title: Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Oncology, Akershus University Hospital, Lørenskog, Norway.|Institute of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway.
authors.forename: Erta
authors.initials: E
authors.lastname: Kalanxhi
authors.affiliation: Department of Oncology, Akershus University Hospital, Lørenskog, Norway.|Institute of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway.
authors.forename: Karianne
authors.initials: K
authors.lastname: Risberg
authors.affiliation: Institute of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Imon S
authors.initials: IS
authors.lastname: Barua
authors.affiliation: Department of Oncology, Oslo University Hospital, Oslo, Norway.
authors.forename: Svein
authors.initials: S
authors.lastname: Dueland
authors.affiliation: Department of Tumour Biology, Oslo University Hospital, Oslo, Norway.
authors.forename: Stein
authors.initials: S
authors.lastname: Waagene
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Department of Pathology, Akershus University Hospital, Lørenskog, Norway.
authors.forename: Solveig Norheim
authors.initials: SN
authors.lastname: Andersen
authors.affiliation: Department of Tumour Biology, Oslo University Hospital, Oslo, Norway.
authors.forename: Solveig J
authors.initials: SJ
authors.lastname: Pettersen
authors.affiliation: Institute of Clinical Molecular Biology, Akershus University Hospital, Lørenskog, Norway.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Lindvall
authors.affiliation: Department of Oncology, Akershus University Hospital, Lørenskog, Norway.
authors.forename: Kathrine Røe
authors.initials: KR
authors.lastname: Redalen
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Department of Tumour Biology, Oslo University Hospital, Oslo, Norway.|Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway.
authors.forename: Kjersti
authors.initials: K
authors.lastname: Flatmark
authors.affiliation: Department of Oncology, Akershus University Hospital, Lørenskog, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Anne Hansen
authors.initials: AH
authors.lastname: Ree
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015415:Biomarkers; D002460:Cell Line; D017321:Clinical Trials, Phase I as Topic; D003131:Combined Modality Therapy; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D010388:Pelvis / Q000528:radiation effects; D011878:Radiotherapy / Q000379:methods; D051381:Rats; D059467:Transcriptome; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat
keywords: Apoptosis; Drug-related side effects and adverse reactions; Histone deacetylase inhibitors; Phase I Clinical Trials; Radiotherapy