TY - JOUR
T1 - A nonhuman primate model of human radiation-induced venocclusive liver disease and hepatocyte injury
AU - Yannam, Govardhana Rao
AU - Han, Bing
AU - Setoyama, Kentaro
AU - Yamamoto, Toshiyuki
AU - Ito, Ryotaro
AU - Brooks, Jenna M.
AU - Guzman-Lepe, Jorge
AU - Galambos, Csaba
AU - Fong, Jason V.
AU - Deutsch, Melvin
AU - Quader, Mubina A.
AU - Yamanouchi, Kosho
AU - Kabarriti, Rafi
AU - Mehta, Keyur
AU - Soto-Gutierrez, Alejandro
AU - Roy-Chowdhury, Jayanta
AU - Locker, Joseph
AU - Abe, Michio
AU - Enke, Charles A.
AU - Baranowska-Kortylewicz, Janina
AU - Solberg, Timothy D.
AU - Guha, Chandan
AU - Fox, Ira J.
N1 - Funding Information:
This work was supported by National Institutes of Health grants RO1s DK46057 , DK67440 , and DK68216 (to JRC); DOD PC102137 (to TDS); R01 DK64670 and R21/R33 CA121051 (to CG); and RO1s AI49472 , and DK48794 (to IJF).
PY - 2014/2/1
Y1 - 2014/2/1
N2 - Background Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.
AB - Background Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.
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U2 - 10.1016/j.ijrobp.2013.10.037
DO - 10.1016/j.ijrobp.2013.10.037
M3 - Article
C2 - 24315566
AN - SCOPUS:84891860087
SN - 0360-3016
VL - 88
SP - 404
EP - 411
JO - International Journal of Radiation Oncology Biology Physics
JF - International Journal of Radiation Oncology Biology Physics
IS - 2
ER -