Abstract 2821: Mitigation of radiation-induced colon injuries in mice by oral sepiapterin (PTC923)

Abstract The rectum is the primary dose limiting structure for radiation therapy (RT) in treating prostate cancer. Two clinical forms of rectal injury have been described: early and late. Early injury typically develops during RT and occurs to some degree in most patients. The condition is usually self-limiting, but can predispose patients to the development of late injury. Late rectal injury occurs in up to 25% of patients months to years after pelvic RT and is more concerning, since it can be irreversible and can have a major impact on a patient’s lifestyle. Development of new pharmacologic approaches to eliminate the risk of RT-dependent rectal injury remains an important goal. Although detailed mechanisms underlying normal tissue toxicities vary from tissue to tissue, the central underlying mechanism is abnormal wound healing involving endothelial dysfunction (ED) and subsequently fibrosis. Regardless of its cause, ED is characterized by an “uncoupled” endothelial NOS (eNOS) activity that generates superoxide (O2 -) and peroxynitrite (ONOO-) rather than NO. One mechanism for uncoupling in inflammatory conditions is oxidation of the reduced cofactor tetrahydrobiopterin (BH4). The product of uncoupling, ONOO-, oxidizes BH4, initiating a feed forward mechanism to sustain uncoupling. Oral treatment with sepiapterin (PTC923), a tetrahydrobiopterin precursor, decreased infiltrating inflammatory cells and cytokine levels in mice with colitis. We therefore tested whether a synthetic PTC923 might mitigate radiation-induced colon injuries. C57L/J wild-type 6-8-week-old males mice received 13.5 Gy total-body irradiation (TBI). Starting from 24 h post-irradiation, mice were treated once daily with 1 mg/kg PTC923 for six days by oral gavage. Colon injuries were accessed on 6th day after IR by colonoscopy and scored by using distal-proximal endoscopic colitis scoring system (D-PECS). The system has a core inflammatory component of four non-co-linear parameters and decimal units to notable lesions or complications. Relative expression of cytokines IL-1β, IL-6, IL-17α, and TGF-β1 in colon endothelial cells were measured by RT-PCR 8 days after IR. According with D-PECS estimation, post-irradiation colon injury was significantly reduced by PTC923 treatment: on the 6th day after TBI mice demonstrated D-PECS score 5.8±1.48 vs 1.6±0.55 D-PECS score for animals received PTC923 treatment after TBI (p-value=0.00). Increase of cytokines IL-6 and TGF-β1 in the colon endothelium after TBI was effectively blocked by PTC923 treatment (IL-6: IR+Vehicle = 4.31±1.31 fold increase vs IR+PTC923 = 1.29±0.37 fold increase (p-value=0.0016); TGF-β1: IR+Vehicle = 5.18±0.66 fold increase vs IR+PTC923 = 2.01±0.75 fold increase (p-value=0.00029)). In conclusion, these findings support the proposal that oral treatment with sepiapterin is a potential mitigator of colon injury caused by RT. Citation Format: Vasily A. Yakovlev, Christopher S. Rabender, Ross B. Mikkelsen. Mitigation of radiation-induced colon injuries in mice by oral sepiapterin (PTC923) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2821.