Prolyl Hydroxylase Inhibition Protects Against Gastrointestinal Radiation Toxicity

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In a study reported in Science Translational Medicine, Taniguchi and colleagues found that inhibition of prolyl hydroxylase by genetic knockout or inhibition of all prolyl hydroxylase domain isoforms by the small-molecule dimethyloxallyl glycine (DMOG) resulted in promotion of protection against radiation-induced gastrointestinal toxicity. The protective effects observed in animal models included increased hypoxia-inducible factor (HIF) expression, improved epithelial integrity, reduced apoptosis, and increased intestinal angiogenesis.

It was shown that HIF2 but not HIF1 is both necessary and sufficient to prevent radiation-induced gastrointestinal toxicity and death. Increased vascular endothelial growth factor (VEGF) expression was found to contribute to the protective effects of HIF2, with VEGF inhibition reversing the protective effects induced by DMOG. Mortality from abdominal or total body irradiation was reduced even when DMOG was given 24 hours after exposure.

The investigators concluded, “[P]rolyl hydroxylase inhibition represents a treatment strategy to protect against and mitigate [gastrointestinal] toxicity from both therapeutic radiation and potentially lethal radiation exposures.” ■

Taniguchi CM, et al: Sci Transl Med 6:236ra64, 2014.




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