Enteral Activation of WR-2721 Mediates Radioprotection and Improved Survival from Lethal Fractionated Radiation
| Autor: | Carolina J. Garcia Garcia, James M. Tour, Wai Kin Chan, Aaron J. Grossberg, Tara N. Fujimoto, Philip L. Lorenzi, Robert Dantzer, Daniel Lin, Thomas D. Horvath, Jessica M. Molkentine, Cullen M. Taniguchi, Kathy A. Mason, Marimar de la Cruz Bonilla, Errol L. G. Samuel, Helen Piwnica-Worms, Amit Deorukhkar |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine medicine.medical_treatment lcsh:Medicine Administration Oral Radiation-Protective Agents Radiation Dosage Enteral administration Article Mice 03 medical and health sciences Amifostine Radiation Protection 0302 clinical medicine Oral administration Pancreatic cancer Intestine Small medicine Animals lcsh:Science Multidisciplinary business.industry lcsh:R Cancer medicine.disease Mercaptoethylamines Small intestine 3. Good health Mice Inbred C57BL Pancreatic Neoplasms Radiation therapy 030104 developmental biology medicine.anatomical_structure Duodenum Cancer research lcsh:Q Female business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Scientific Reports Scientific Reports, Vol 9, Iss 1, Pp 1-11 (2019) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-018-37147-9 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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