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

Radiat Oncol. 2012 Sep 27;7:165. doi: 10.1186/1748-717X-7-165.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Capecitabine
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / radiotherapy
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Female
  • Fluorouracil / administration & dosage
  • Fluorouracil / analogs & derivatives
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Humans
  • Hydroxamic Acids / administration & dosage
  • Hypoxia*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Radiation Tolerance / drug effects*
  • Radiation-Sensitizing Agents / therapeutic use*
  • Tumor Cells, Cultured
  • Vorinostat

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Radiation-Sensitizing Agents
  • Deoxycytidine
  • Vorinostat
  • Capecitabine
  • Fluorouracil