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Title: Radiation-Associated Liver Injury

Abstract

The liver is a critically important organ that has numerous functions including the production of bile, metabolism of ingested nutrients, elimination of many waste products, glycogen storage, and plasma protein synthesis. The liver is often incidentally irradiated during radiation therapy (RT) for tumors in the upper- abdomen, right lower lung, distal esophagus, or during whole abdomen or whole body RT. This article describes the endpoints, time-course, and dose-volume effect of radiation on the liver.

Authors:
 [1];  [2];  [3];  [4];  [5];  [2];  [1]
  1. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI (United States)
  2. Department of Radiation Oncology, University of Colorado, Aurora, CO (United States)
  3. Princess Margaret Hospital, University of Toronto, Toronto, Ontario (Canada)
  4. Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI (United States)
  5. Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States)
Publication Date:
OSTI Identifier:
21372136
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 76; Journal Issue: 3; Other Information: DOI: 10.1016/j.ijrobp.2009.06.092; PII: S0360-3016(09)03295-7; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ABDOMEN; ESOPHAGUS; LIVER; NEOPLASMS; RADIATION INJURIES; RADIOTHERAPY; BIOLOGICAL EFFECTS; BIOLOGICAL RADIATION EFFECTS; BODY; DIGESTIVE SYSTEM; DISEASES; GLANDS; INJURIES; MEDICINE; NUCLEAR MEDICINE; ORGANS; RADIATION EFFECTS; RADIOLOGY; THERAPY

Citation Formats

Pan, Charlie C., E-mail: cpan@umich.ed, Kavanagh, Brian D., Dawson, Laura A., Li, X. Allen, Das, Shiva K., Miften, Moyed, and Ten Haken, Randall K. Radiation-Associated Liver Injury. United States: N. p., 2010. Web. doi:10.1016/j.ijrobp.2009.06.092.
Pan, Charlie C., E-mail: cpan@umich.ed, Kavanagh, Brian D., Dawson, Laura A., Li, X. Allen, Das, Shiva K., Miften, Moyed, & Ten Haken, Randall K. Radiation-Associated Liver Injury. United States. doi:10.1016/j.ijrobp.2009.06.092.
Pan, Charlie C., E-mail: cpan@umich.ed, Kavanagh, Brian D., Dawson, Laura A., Li, X. Allen, Das, Shiva K., Miften, Moyed, and Ten Haken, Randall K. 2010. "Radiation-Associated Liver Injury". United States. doi:10.1016/j.ijrobp.2009.06.092.
@article{osti_21372136,
title = {Radiation-Associated Liver Injury},
author = {Pan, Charlie C., E-mail: cpan@umich.ed and Kavanagh, Brian D. and Dawson, Laura A. and Li, X. Allen and Das, Shiva K. and Miften, Moyed and Ten Haken, Randall K.},
abstractNote = {The liver is a critically important organ that has numerous functions including the production of bile, metabolism of ingested nutrients, elimination of many waste products, glycogen storage, and plasma protein synthesis. The liver is often incidentally irradiated during radiation therapy (RT) for tumors in the upper- abdomen, right lower lung, distal esophagus, or during whole abdomen or whole body RT. This article describes the endpoints, time-course, and dose-volume effect of radiation on the liver.},
doi = {10.1016/j.ijrobp.2009.06.092},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 3,
volume = 76,
place = {United States},
year = 2010,
month = 3
}
  • A large number of antibiotics are known to cause drug-induced liver injury in the clinic; however, interpreting clinical risk is not straightforward owing to a lack of predictivity of the toxicity by standard preclinical species and a poor understanding of the mechanisms of toxicity. An example is PF-04287881, a novel ketolide antibiotic that caused elevations in liver function tests in Phase I clinical studies. In this study, a mouse diversity panel (MDP), comprised of 34 genetically diverse, inbred mouse strains, was utilized to model the toxicity observed with PF-04287881 treatment and investigate potential mechanisms that may mediate the liver response.more » Significant elevations in serum alanine aminotransferase (ALT) levels in PF-04287881-treated animals relative to vehicle-treated controls were observed in the majority (88%) of strains tested following a seven day exposure. The average fold elevation in ALT varied by genetic background and correlated with microscopic findings of hepatocellular hypertrophy, hepatocellular single cell necrosis, and Kupffer cell vacuolation (confirmed as phospholipidosis) in the liver. Global liver mRNA expression was evaluated in a subset of four strains to identify transcript and pathway differences that distinguish susceptible mice from resistant mice in the context of PF-04287881 treatment. The protein ubiquitination pathway was highly enriched among genes associated with PF-04287881-induced hepatocellular necrosis. Expression changes associated with PF-04287881-induced phospholipidosis included genes involved in drug transport, phospholipid metabolism, and lysosomal function. The findings suggest that perturbations in genes involved in protein degradation leading to accumulation of oxidized proteins may mediate the liver injury induced by this drug. - Highlights: • Identified susceptible and resistant mouse strains to liver injury induced by a CAD • Liver injury characterized by single cell necrosis, and phospholipidosis • Decreased gene expression associated with protein ubiquitination in sensitive mice • Altered protein ubiquitination may cause oxidized protein accumulation in the liver.« less
  • Purpose: To investigate whether pravastatin mitigates delayed radiation-induced enteropathy in rats, by focusing on the effects of pravastatin on acute cell death and fibrosis according to connective tissue growth factor (CTGF) expression and collagen inhibition. Methods and Materials: Mitigation of delayed radiation-induced enteropathy was investigated in rats using pravastatin administered in drinking water (30 mg/kg/day) 3 days before and 14 days after irradiation. The ileum was irradiated locally after surgical exteriorization (X-rays, 19 Gy). Acute apoptosis, acute and late histologic alterations, and late CTGF and collagen deposition were monitored by semiquantitative immunohistochemistry and colorimetric staining (6 h, 3 days, 14more » days, 15 weeks, and 26 weeks after irradiation). Pravastatin antitumor action was studied in HT-29, HeLa, and PC-3 cells by clonogenic cell survival assays and tumor growth delay experiments. Results: Pravastatin improved delayed radiation enteropathy in rats, whereas its benefit in acute and subacute injury remained limited (6 h, 3 days, and 14 days after irradiation). Delayed structural improvement was associated with decreased CTGF and collagen deposition but seemed unrelated to acute damage. Indeed, the early apoptotic index increased, and severe subacute structural damage occurred. Pravastatin elicited a differential effect, protecting normal intestine but not tumors from radiation injury. Conclusion: Pravastatin provides effective protection against delayed radiation enteropathy without interfering with the primary antitumor action of radiotherapy, suggesting that clinical transfer is feasible.« less