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

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dc.citation.articleNumber1949
dc.citation.journalTitleScientific Reports
dc.citation.volumeNumber9
dc.contributor.authorMolkentine, Jessica M.
dc.contributor.authorFujimoto, Tara N.
dc.contributor.authorHorvath, Thomas D.
dc.contributor.authorGrossberg, Aaron J.
dc.contributor.authorGarcia, Carolina J. Garcia
dc.contributor.authorDeorukhkar, Amit
dc.contributor.authorde la Cruz Bonilla, Marimar
dc.contributor.authorLin, Daniel
dc.contributor.authorSamuel, Errol L.G.
dc.contributor.authorChan, Wai Kin
dc.contributor.authorLorenzi, Philip L.
dc.contributor.authorPiwnica-Worms, Helen
dc.contributor.authorDantzer, Robert
dc.contributor.authorTour, James M.
dc.contributor.authorMason, Kathryn A.
dc.contributor.authorTaniguchi, Cullen M.
dc.date.accessioned2019-12-12T17:25:43Z
dc.date.available2019-12-12T17:25:43Z
dc.date.issued2019
dc.description.abstractUnresectable 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.
dc.identifier.citationMolkentine, Jessica M., Fujimoto, Tara N., Horvath, Thomas D., et al.. "Enteral Activation of WR-2721 Mediates Radioprotection and Improved Survival from Lethal Fractionated Radiation." <i>Scientific Reports,</i> 9, (2019) Springer Nature: https://doi.org/10.1038/s41598-018-37147-9.
dc.identifier.digitals41598-018-37147-9
dc.identifier.doihttps://doi.org/10.1038/s41598-018-37147-9
dc.identifier.urihttps://hdl.handle.net/1911/107897
dc.language.isoeng
dc.publisherSpringer Nature
dc.rightsThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleEnteral Activation of WR-2721 Mediates Radioprotection and Improved Survival from Lethal Fractionated Radiation
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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