Radiosensitization by diamide analogs and arsenicals

Area of Science:

• Cellular and Molecular Radiobiology
• Biochemistry

Background:

• Glutathione (GSH) is a key cellular reducing agent involved in protecting cells from oxidative stress.
• Diamide and its analogs are reagents that oxidize GSH, potentially impacting cellular radiosensitivity.

Purpose of the Study:

• To investigate the radiosensitizing potential of diamide analogs, focusing on SR-4077.
• To elucidate the mechanism by which GSH oxidizing reagents sensitize aerobic cells to X-ray irradiation.

Main Methods:

• Testing of several diamide analogs as radiosensitizers in aerobic cells.
• Assessment of SR-4077's radiosensitizing effects on Chinese Hamster Ovary (CHO) cells, including post-irradiation drug addition.
• Evaluation of phenylarsine oxide's effect on cell survival curves.

Main Results:

• Radiosensitization generally correlated with the rate of reaction with cellular reducing agents, occurring when cellular reductive capacity was exceeded.
• SR-4077 demonstrated radiosensitizing effects on aerobic CHO cells, altering both the slope and shoulder of the radiation cell survival curve.
• Phenylarsine oxide also sensitized aerobic CHO cells, specifically modifying the shoulder of the survival curve.

Conclusions:

• The findings support the hypothesis that GSH oxidizing agents sensitize cells by depleting protein thiols.
• These protein thiols are likely involved in the repair of X-ray-induced DNA damage, explaining the observed radiosensitization.
• SR-4077 is a valuable tool for mechanistic studies due to its efficacy and reduced cytotoxicity compared to diamide.