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Abstract
Most cancer patients are treated with radiotherapy, but the treatment can also damage the surrounding normal tissue. Radiotherapy side-effects diminish patients’ quality of life, yet effective biological interventions for normal tissue damage are lacking. Protecting microvascular endothelial cells from the effects of irradiation is emerging as a targeted damage-reduction strategy. We illustrate the concept of the microvasculature as a mediator of overall normal tissue radiation toxicity through cell death, vascular inflammation (hemodynamic and molecular changes) and a change in functional capacity. Endothelial cell targeted therapies that protect against such endothelial cell perturbations and the development of acute normal tissue damage are mostly under preclinical development. Since acute radiation toxicity is a common clinical problem in cutaneous, gastrointestinal and mucosal tissues, we also focus on damage in these tissues.
Highlights
Despite technology-driven improvements in cancer radiotherapy (RT), normal tissue radiation toxicities remain a significant clinical concern [1]
We argue that protecting microvascular endothelial cells from radiation-induced perturbations, or disruptions to the normal homeostatic or angiogenic state, protects the normal tissue from radiation damage
We reported that Vasculotide reduced the severity of ionizing radiation (IR)-induced radiodermatitis in mice, and this was accompanied by lower oxygenated hemoglobin (oxyHb) measurements than in irradiated controls [63]
Summary
Despite technology-driven improvements in cancer radiotherapy (RT), normal tissue radiation toxicities remain a significant clinical concern [1]. We argue that protecting microvascular endothelial cells from radiation-induced perturbations, or disruptions to the normal homeostatic or angiogenic state, protects the normal tissue from radiation damage These perturbations include EC death, vascular inflammation (hemodynamic and molecular changes) and loss of functional capacity. In a landmark study of radiation-induced GI toxicity, Paris et al demonstrated that bFGF treatment and ASMase deficiency both decreased EC apoptosis and improved survival from GI syndrome following TBI [33] This effect was observed with an EC-protecting Angiopoietin-1-based construct, which promotes EC viability and stability [42]. Holler et al reported that pravastatin treatment mitigated 40 Gy acute skin radiation damage severity through diminished EC activation (ICAM-1 expression, etc.) and less neutrophil recruitment [86] These results demonstrate that suppressing aspects of the inflammatory response to radiation, especially in regard to EC activation, can attenuate damage to normal tissues. Blood vessels in irradiated mouse hind limbs treated with an antiCD47 morpholino retain this important function [47]
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