Significance of endothelial dysfunction in the pathogenesis of early and delayed radiation enteropathy

Berbée, M., Fu, Q., Boerma, M., Wang, J., Kumar, K. S. and Hauer-Jensen, M. γ-Tocotrienol Ameliorates Intestinal Radiation Injury and Reduces Vascular Oxidative Stress after Total-Body Irradiation by an HMG-CoA Reductase-Dependent Mechanism. Radiat. Res. 171, 596–605 (2009).Analogs of vitamin E (tocols) are under development as radioprophylactic agents because of their high efficacy and lack of toxicity. Gamma-tocotrienol (GT3) is of particular interest because, in addition to being an antioxidant, it also inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and accumulates to greater extent in endothelial cells than other tocols. We addressed in vivo whether HMG-CoA reductase inhibition contributes to the radioprotection conferred by GT3. Groups of mice were treated with vehicle, mevalonate (the product of the reaction catalyzed by HMG-CoA reductase), GT3 alone or GT3 in combination with mevalonate. Lethality and standard parameters of injury to the hematopoietic, intestinal and vascular/endothelial systems were assessed after exposure to total-body irradiation. GT3 improved postirradiation survival and decreased radiation-induced vascular oxidative stress, an effect that was reversible by mevalonate. GT3 also enhanced hematopoietic recovery, reduced intestinal radiation injury, and accelerated the recovery of soluble markers of endothelial function. These parameters were not reversed by mevalonate co-administration. Our data confirm GT3's radioprophylactic properties against hematopoietic injury and, for the first time, demonstrate benefits in terms of protection against gastrointestinal and vascular injury. The radioprotective efficacy of GT3 against vascular injury is related to its properties as an HMG-CoA reductase inhibitor.

To summarize current knowledge about gastrointestinal radiation toxicity, with emphasis on mechanisms and clinical diagnosis and management. While there has been only modest change in cancer incidence and cancer mortality rates during the past 30 years, the number of cancer survivors has more than doubled. Moreover, the recognition of uncomplicated cancer cure as the ultimate goal in oncology has intensified efforts to prevent, diagnose, and manage side effects of radiation therapy. These efforts have been facilitated by recent insight into the underlying pathophysiology. The risk of injury to the intestine is dose limiting during abdominal and pelvic radiation therapy. Delayed bowel toxicity is difficult to manage and adversely impacts the quality of life of cancer survivors. More than 200,000 patients per year receive abdominal or pelvic radiation therapy, and the estimated number of cancer survivors with postradiation intestinal dysfunction is 1.5-2 million. Worthwhile progress towards reducing toxicity of radiation therapy has been made by dose-sculpting treatment techniques. Approaches derived from an improved understanding of the pathophysiology of bowel injury, however, will result in further advances. This article discusses the mechanisms of radiation-induced bowel toxicity and reviews current principles in diagnosis and management.

To summarize current knowledge regarding the role of the thrombomodulin (TM)-protein C system in acute and chronic radiation responses in normal tissues. Studies published in the biomedical literature during the past three decades and cited in PubMed and unpublished clinical and laboratory data from our own research program. The risk of injury to normal tissues limits the cancer cure rates that can be achieved with radiation therapy. Microvascular injury is a prominent feature of normal tissue radiation injury and plays a critical role in both acute (inflammatory) and chronic (fibrotic) radiation responses. Evidence from our own and other laboratories strongly suggests that dysfunction of the TM–protein C system plays a key role in the pathogenesis of radiation-induced injury to normal tissue. Exposure of normal tissues to ionizing radiation causes a pronounced, sustained deficiency of endothelial TM. This is likely to be due to a combination of initial inactivation of TM by reactive oxygen species, reduced transcription of TM, and release of TM into the circulation. Deficient levels of endothelial TM cause loss of local vascular thrombo-resistance, excessive activation of protease-activated receptor-1 by thrombin, and insufficient activation of protein C. These changes are presumed to be critically involved in many aspects of acute radiation toxicity and in sustaining the fibroproliferative processes that lead to chronic radiation-induced organ dysfunction and clinical complications. Injury of vascular endothelium may be key to the acute responses of normal tissues to ionizing radiation and to the progressive nature of chronic radiation fibrosis. Restitution of the TM–protein C pathway is an appealing strategy by which to prevent or treat normal tissue toxicity associated with radiation treatment of cancer.