Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy / Journal of the Korean Cancer Association, 대한암학회지
Cancer Research and Treatment
;
: 374-386, 2017.
Artigo
em Inglês
| WPRIM
| ID: wpr-101945
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 ANDMETHODS:
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.
Texto completo:
DisponíveL
Índice:
WPRIM (Pacífico Ocidental)
Assunto principal:
Radioterapia
/
Histonas
/
Redução de Peso
/
Expressão Gênica
/
Células Cultivadas
/
Estudos de Coortes
/
Ensaios Clínicos Fase I como Assunto
/
Apoptose
/
Análise em Microsséries
/
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos
Tipo de estudo:
Estudo de etiologia
/
Estudo de incidência
/
Estudo observacional
/
Fatores de risco
Limite:
Animais
/
Humanos
Idioma:
Inglês
Revista:
Cancer Research and Treatment
Ano de publicação:
2017
Tipo de documento:
Artigo
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