Enteral Activation of WR-2721 Mediates Radioprotection and Improved Survival from Lethal Fractionated Radiation

Abstract

Unresectable pancreatic cancer is almost universally lethal because chemotherapy and radiation cannot completely stop the growth of the cancer. The major problem with using radiation to approximate surgery in unresectable disease is that the radiation dose required to ablate pancreatic cancer exceeds the tolerance of the nearby duodenum. WR-2721, also known as amifostine, is a well-known radioprotector, but has significant clinical toxicities when given systemically. WR-2721 is a prodrug and is converted to its active metabolite, WR-1065, by alkaline phosphatases in normal tissues. The small intestine is highly enriched in these activating enzymes, and thus we reasoned that oral administration of WR-2721 just before radiation would result in localized production of the radioprotective WR-1065 in the small intestine, providing protective benefits without the significant systemic side effects. Here, we show that oral WR-2721 is as effective as intraperitoneal WR-2721 in promoting survival of intestinal crypt clonogens after morbid irradiation. Furthermore, oral WR-2721 confers full radioprotection and survival after lethal upper abdominal irradiation of 12.5 Gy × 5 fractions (total of 62.5 Gy, EQD2 = 140.6 Gy). This radioprotection enables ablative radiation therapy in a mouse model of pancreatic cancer and nearly triples the median survival compared to controls. We find that the efficacy of oral WR-2721 stems from its selective accumulation in the intestine, but not in tumors or other normal tissues, as determined by in vivo mass spectrometry analysis. Thus, we demonstrate that oral WR-2721 is a well-tolerated, and quantitatively selective, radioprotector of the intestinal tract that is capable of enabling clinically relevant ablative doses of radiation to the upper abdomen without unacceptable gastrointestinal toxicity.

Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer

“…000664) were purchased from The Jackson Laboratory. Kras LSL/+ and Trp53 FL/FL ; Ptf1a Cre/+ animals were backcrossed to a pure C57BL/6 background as previously described (48).…”

Nuclear and Radiological Emergencies: Biological Effects, Countermeasures and Biodosimetry

“…Undoubtedly, the most effective was WR-2721 or amifostine, a sulfhydryl prodrug activated by alkaline phosphatase to the active WR-1065. Salivary glands and the epithelial cells of intestine are highly enriched in this activating enzyme, and thus oral administration of WR-2721 just before radiation results in localized high production of the bioactive derivate, preventing radio-induced mucositis and GI damage without significant systemic side effects [ 86 , 87 , 88 , 89 ]. The underlying mechanisms of action are free radical scavenging and hydrogen atom donation, along with DNA protection and repair; all coupled to an initial induction of cellular hypoxia [ 90 , 91 , 92 ].…”

MicroRNAs as Biomarkers for Ionizing Radiation Injury

“…Afterwards, this study elucidated the correlation between miRNAs and the degree of radiation damage. They used the radioprotective agent amifostine, which is known to prolong survival in mice and humans by reducing radiation-related toxicity ( Pamujula et al, 2005 ; Molkentine et al, 2019 ; Singh and Seed, 2019 ), to inject mice intraperitoneally prior to irradiation. The results showed that all mice in the amifostine injection group (before IR) survived, and all the mentioned miRNAs above were significantly altered compared to the saline injection group (before IR), suggesting that this group of miRNAs was related to the ability to survive (or the degree of damage suffered) and not the radiation dose.…”