Cancer Therapy: Preclinical Darinaparsin: Solid Tumor Hypoxic Cytotoxin and Radiosensitizer

Purpose:Hypoxia is an important characteristic of the solid tumor microenvironment and constitutes a barrier for effective radiotherapy. Here, we studied the effects of darinaparsin (an arsenic cytotoxin) on survival and radiosensitivity of tumor cells in vitro under normoxia and hypoxia and in vivo using xenograft models, compared to effects on normal tissues. ExperimentalDesign:The cytotoxicity and radiosensitization of darinaparsinwere first tested in vitro in a variety of solid tumor cell lines under bothnormoxia andhypoxia and comparedwith arsenic trioxide (ATO, an arsenical with reported cytotoxic and radiosensitizing activities on tumor cells). The effects were then tested inmousemodels of xenograft tumors derived from tumor cell lines and clinical tumor specimens. The potential mechanisms of darinaparsin effects, including reactive oxygen species (ROS) generation, cellular damage, and changes in global gene expression, were also investigated. Results: In comparison with ATO, darinaparsin had significantly higher in vitro cytotoxic and radiosensitizing activities against solid tumor cells under both normoxia and hypoxia. In vivo experiments confirmed these activities at doses that had no systemic toxicities. Importantly, darinaparsin did not radiosensitize normal bonemarrow and actually radioprotected normal intestinal crypts. The darinaparsinmediated antitumor effects under hypoxia were not dependent on ROS generation and oxidative damage, but were associated with inhibition of oncogene (RAS and MYC)-dependent gene expression. Conclusion:Darinaparsin has significant and preferential cytotoxic and radiosensitizing effects on solid tumors as compared with normal cells. Darinaparsin may therefore increase the therapeutic index of radiation therapy and has near term translational potential. Clin Cancer Res; 1–11. 2012 AACR.