Darinaparsin: solid tumor hypoxic cytotoxin and radiosensitizer.

Abstract

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.

EXPERIMENTAL DESIGN:

The cytotoxicity and radiosensitization of darinaparsin were first tested in vitro in a variety of solid tumor cell lines under both normoxia and hypoxia and compared with arsenic trioxide (ATO, an arsenical with reported cytotoxic and radiosensitizing activities on tumor cells). The effects were then tested in mouse models 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 bone marrow and actually radioprotected normal intestinal crypts. The darinaparsin-mediated 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.

• Authors: Junqiang Tian, Hongjuan Zhao, Rosalie Nolley, Stephen W Reese, Sarah R Young, Xuejun Li, Donna M Peehl, Susan J Knox
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 12 Pg. 3366-76 (Jun 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22535156 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Arsenicals
• Oxides
• Proto-Oncogene Proteins c-myc
• Radiation-Sensitizing Agents
• Reactive Oxygen Species
• darinaparsin
• Proto-Oncogene Proteins p21(ras)
• Glutathione
• Arsenic Trioxide

Topics

• Animals
• Apoptosis (drug effects, radiation effects)
• Arsenic Trioxide
• Arsenicals (pharmacology)
• Bone Marrow (drug effects, radiation effects)
• Cell Hypoxia
• Glutathione (analogs & derivatives, pharmacology)
• Humans
• Intestines (drug effects, radiation effects)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasms (drug therapy, radiotherapy)
• Oxides (pharmacology)
• Proto-Oncogene Proteins c-myc (genetics)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Radiation-Sensitizing Agents (pharmacology)
• Reactive Oxygen Species (metabolism)
• Xenograft Model Antitumor Assays