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

Jessica M. Molkentine, Tara N. Fujimoto, Thomas D. Horvath, Aaron Grossberg, Carolina J.Garcia Garcia, Amit Deorukhkar, Marimar de la Cruz Bonilla, Daniel Lin, Errol L.G. Samuel, Wai Kin Chan, Philip L. Lorenzi, Helen Piwnica-Worms, Robert Dantzer, James M. Tour, Kathryn A. Mason, Cullen M. Taniguchi

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Article number1949
JournalScientific Reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019
Externally publishedYes

Fingerprint

Amifostine
Small Intestine
Radiation
Pancreatic Neoplasms
Prodrugs
Duodenum
Abdomen
Intestines
Alkaline Phosphatase
Oral Administration
Mass Spectrometry
Neoplasms
Radiotherapy
Drug Therapy

ASJC Scopus subject areas

  • General

Cite this

Molkentine, J. M., Fujimoto, T. N., Horvath, T. D., Grossberg, A., Garcia, C. J. G., Deorukhkar, A., ... Taniguchi, C. M. (2019). Enteral Activation of WR-2721 Mediates Radioprotection and Improved Survival from Lethal Fractionated Radiation. Scientific Reports, 9(1), [1949]. https://doi.org/10.1038/s41598-018-37147-9

Enteral Activation of WR-2721 Mediates Radioprotection and Improved Survival from Lethal Fractionated Radiation. / Molkentine, Jessica M.; Fujimoto, Tara N.; Horvath, Thomas D.; Grossberg, Aaron; Garcia, Carolina J.Garcia; Deorukhkar, Amit; de la Cruz Bonilla, Marimar; Lin, Daniel; Samuel, Errol L.G.; Chan, Wai Kin; Lorenzi, Philip L.; Piwnica-Worms, Helen; Dantzer, Robert; Tour, James M.; Mason, Kathryn A.; Taniguchi, Cullen M.

In: Scientific Reports, Vol. 9, No. 1, 1949, 01.12.2019.

Research output: Contribution to journalArticle

Molkentine, JM, Fujimoto, TN, Horvath, TD, Grossberg, A, Garcia, CJG, Deorukhkar, A, de la Cruz Bonilla, M, Lin, D, Samuel, ELG, Chan, WK, Lorenzi, PL, Piwnica-Worms, H, Dantzer, R, Tour, JM, Mason, KA & Taniguchi, CM 2019, 'Enteral Activation of WR-2721 Mediates Radioprotection and Improved Survival from Lethal Fractionated Radiation', Scientific Reports, vol. 9, no. 1, 1949. https://doi.org/10.1038/s41598-018-37147-9
Molkentine, Jessica M. ; Fujimoto, Tara N. ; Horvath, Thomas D. ; Grossberg, Aaron ; Garcia, Carolina J.Garcia ; Deorukhkar, Amit ; de la Cruz Bonilla, Marimar ; Lin, Daniel ; Samuel, Errol L.G. ; Chan, Wai Kin ; Lorenzi, Philip L. ; Piwnica-Worms, Helen ; Dantzer, Robert ; Tour, James M. ; Mason, Kathryn A. ; Taniguchi, Cullen M. / Enteral Activation of WR-2721 Mediates Radioprotection and Improved Survival from Lethal Fractionated Radiation. In: Scientific Reports. 2019 ; Vol. 9, No. 1.
@article{8360d70ece3f4483b6a57d68c2725313,
title = "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.",
author = "Molkentine, {Jessica M.} and Fujimoto, {Tara N.} and Horvath, {Thomas D.} and Aaron Grossberg and Garcia, {Carolina J.Garcia} and Amit Deorukhkar and {de la Cruz Bonilla}, Marimar and Daniel Lin and Samuel, {Errol L.G.} and Chan, {Wai Kin} and Lorenzi, {Philip L.} and Helen Piwnica-Worms and Robert Dantzer and Tour, {James M.} and Mason, {Kathryn A.} and Taniguchi, {Cullen M.}",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41598-018-37147-9",
language = "English (US)",
volume = "9",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Enteral Activation of WR-2721 Mediates Radioprotection and Improved Survival from Lethal Fractionated Radiation

AU - Molkentine, Jessica M.

AU - Fujimoto, Tara N.

AU - Horvath, Thomas D.

AU - Grossberg, Aaron

AU - Garcia, Carolina J.Garcia

AU - Deorukhkar, Amit

AU - de la Cruz Bonilla, Marimar

AU - Lin, Daniel

AU - Samuel, Errol L.G.

AU - Chan, Wai Kin

AU - Lorenzi, Philip L.

AU - Piwnica-Worms, Helen

AU - Dantzer, Robert

AU - Tour, James M.

AU - Mason, Kathryn A.

AU - Taniguchi, Cullen M.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85061483039&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061483039&partnerID=8YFLogxK

U2 - 10.1038/s41598-018-37147-9

DO - 10.1038/s41598-018-37147-9

M3 - Article

C2 - 30760738

AN - SCOPUS:85061483039

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 1949

ER -