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Abstract
BackgroundThe 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.MethodsRadiosensitization 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.ResultsUnder 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.ConclusionsVorinostat 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.
Highlights
The histone deacetylase inhibitor vorinostat is a candidate radiosensitizer in locally advanced rectal cancer (LARC)
In a recent clinical phase I study, we reported a favorable toxicity profile of vorinostat in combination with pelvic palliative radiotherapy [8,9]
Radiosensitizing properties of vorinostat in combination with the fluoropyrimidine capecitabine were investigated in two colorectal carcinoma xenograft models
Summary
The histone deacetylase inhibitor vorinostat is a candidate radiosensitizer in locally advanced rectal cancer (LARC). 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. In locally advanced rectal cancer (LARC), neoadjuvant chemoradiotherapy (CRT) is given to obtain tumor downstaging to allow complete surgical removal, and singleagent fluoropyrimidine in combination with fractionated pelvic radiation remains the standard regimen [1]. Since human solid tumors, including rectal carcinomas, often contain a substantial fraction of hypoxic cells that are intrinsically more resistant to radiotherapy, a drug’s ability to radiosensitize tumor cells under hypoxia should be taken into account when investigating new CRT candidates [11]. Since fluoropyrimidine-based CRT is the established regimen in LARC, potential interaction between a new drug and the standard treatment should be investigated to reveal possible antagonistic or synergistic effects. Radiosensitizing properties of vorinostat in combination with the fluoropyrimidine capecitabine were investigated in two colorectal carcinoma xenograft models
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