Radiosensitization by the histone deacetylase inhibitor vorinostat under hypoxia and with capecitabine in experimental colorectal carcinoma

Radiation Oncology

Kjersti Flatmark⁴  Helga Helseth Hektoen¹  Torbjørn Furre²  Karianne Giller Fleten⁴  Alexandr Kristian⁴  Anne Hansen Ree³  Marie Grøn Saelen¹ 

[1] Institute of Clinical Medicine, University of Oslo, Oslo, Norway;Department of Medical Physics, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway;Department of Oncology, Akershus University Hospital, Lørenskog, Norway;Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, P.O. Box 4953, Nydalen, 0424, Oslo, Norway

关键词: Radiation;    Hypoxia;    Fluoropyrimidine;    Vorinostat;    Rectal cancer;   

Others  :  1155251
DOI  :  10.1186/1748-717X-7-165

 received in 2012-04-19, accepted in 2012-09-21,  发布年份 2012

【 摘 要 】

Background

The histone deacetylase inhibitor vorinostat is a candidate radiosensitizer in locally advanced rectal cancer (LARC). Radiosensitivity is critically influenced by hypoxia; hence, it is important to evaluate the efficacy of potential radiosensitizers under variable tissue oxygenation. Since fluoropyrimidine-based chemoradiotherapy (CRT) is the only clinically validated regimen in LARC, efficacy in combination with this established regimen should be assessed in preclinical models before a candidate drug enters clinical trials.

Methods

Radiosensitization by vorinostat under hypoxia was studied in four colorectal carcinoma cell lines and in one colorectal carcinoma xenograft model by analysis of clonogenic survival and tumor growth delay, respectively. Radiosensitizing effects of vorinostat in combination with capecitabine were assessed by evaluation of tumor growth delay in two colorectal carcinoma xenografts models.

Results

Under hypoxia, radiosensitization by vorinostat was demonstrated in vitro in terms of decreased clonogenicity and in vivo as inhibition of tumor growth. Adding vorinostat to capecitabine-based CRT increased radiosensitivity of xenografts in terms of inhibited tumor growth.

Conclusions

Vorinostat sensitized colorectal carcinoma cells to radiation under hypoxia in vitro and in vivo and improved therapeutic efficacy in combination with capecitabine-based CRT in vivo. The results encourage implementation of vorinostat into CRT in LARC trials.

【 授权许可】

   
2012 Saelen et al.; licensee BioMed Central Ltd.

【 图 表 】

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