Sunday, October 31, 2021

Synthetic Triterpenoid RTA‐408: Limits Radiation Damage to Normal Tissue

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Objectives/Hypothesis

To assess the efficacy and mechanism of action of a novel approach to mitigate acute and chronic radiation toxicity in a validated animal model.

Study Design

Randomized, prospective study using an in vivo rat model.

Methods

Experimental animal study utilizing Sprague–Dawley rats divided into three cohorts: 1) radiation + dimethyl sulfoxide (DMSO) (inert vehicle); 2) radiation + RTA-408 (therapeutic drug); and 3) no radiation + DMSO. All animals in the radiation cohorts underwent 40 Gy of radiation with subsequent inferior epigastric axial rotational flap 30 days later in all cohorts with percentage of flap necrosis and vascular density calculated by blinded observers. In a second experiment, an additional three cohorts, underwent serial punch biopsies of the abdominal skin before, during, and after radiation and drug/vehicle control treatment. Transcriptome analysis utilizing gene set enrichment analysis and digital polymerase chain reaction were performed at various time points.

Results

The first experiment revealed average flap necrosis of 20% (95% confidence interval [CI] 16–45) in the radiation control group, 3% (95% CI 0–11) in the nonirradiated control, and 3% (95% CI 0.2–10) in the radiation group treated with RTA-408. Vascular density was preserved in the treatment group as compared to the radiated control. Nine rats were included in the second experiment, and transcriptome analyses in the treatment group revealed robust activation of antioxidant pathways with induced expression of genes associated with hypoxia and adipogenesis/angiogenesis.

Conclusions

Administration of RTA-408 during radiation treatment in a rat model resulted in transcriptome changes which appear to mitigate the toxic effects of radiation, preserving capillary networks and improving flap survival and tissue healing after subsequent surgery.

Level of Evidence

Foundational Evidence, Animal Research Laryngoscope, 2021

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