Vasculotide, an Angiopoietin-1 mimetic, reduces acute skin ionizing radiation damage in a preclinical mouse model

Abstract

BackgroundMost cancer patients are treated with radiotherapy, but the treatment can also damage the surrounding normal tissue. Acute skin damage from cancer radiotherapy diminishes patients’ quality of life, yet effective biological interventions for this damage are lacking. Protecting microvascular endothelial cells from irradiation-induced perturbations is emerging as a targeted damage-reduction strategy. Since Angiopoetin-1 signaling through the Tie2 receptor on endothelial cells opposes microvascular perturbations in other disease contexts, we used a preclinical Angiopoietin-1 mimic called Vasculotide to investigate its effect on skin radiation toxicity using a preclinical model.MethodsAthymic mice were treated intraperitoneally with saline or Vasculotide and their flank skin was irradiated with a single large dose of ionizing radiation. Acute cutaneous damage and wound healing were evaluated by clinical skin grading, histology and immunostaining. Diffuse reflectance optical spectroscopy, myeloperoxidase-dependent bioluminescence imaging of neutrophils and a serum cytokine array were used to assess inflammation. Microvascular endothelial cell response to radiation was tested with in vitro clonogenic and Matrigel tubule formation assays. Tumour xenograft growth delay experiments were also performed. Appreciable differences between treatment groups were assessed mainly using parametric and non-parametric statistical tests comparing areas under curves, followed by post-hoc comparisons.ResultsIn vivo, different schedules of Vasculotide treatment reduced the size of the irradiation-induced wound. Although skin damage scores remained similar on individual days, Vasculotide administered post irradiation resulted in less skin damage overall. Vasculotide alleviated irradiation-induced inflammation in the form of reduced levels of oxygenated hemoglobin, myeloperoxidase bioluminescence and chemokine MIP-2. Surprisingly, Vasculotide-treated animals also had higher microvascular endothelial cell density in wound granulation tissue. In vitro, Vasculotide enhanced the survival and function of irradiated endothelial cells.ConclusionsVasculotide administration reduces acute skin radiation damage in mice, and may do so by affecting several biological processes. This radiation protection approach may have clinical impact for cancer radiotherapy patients by reducing the severity of their acute skin radiation damage.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-614) contains supplementary material, which is available to authorized users.

Diffuse Optical Spectroscopy for the Quantitative Assessment of Acute Ionizing Radiation Induced Skin Toxicity Using a Mouse Model

“…To minimize this limitation, a 5 point quadrant scan that captures the overall irradiated volume was employed. Despite the lack of spatial resolution, previous work in mice 5 has shown the ability of optical biomarkers averaged over a sparse area to differentiate not only irradiated and non-irradiated skin but also the impact of skin sparing interventional drugs such as Vasculotide 6 .…”

“…Blood hemoglobin (Hb), tissue oxygen saturation (StO 2 ) or oxygenated hemoglobin (oxyHb) levels have been used as proxies for irradiation-induced erythema in mice [3][4][5][6] . Following irradiation, total Hb levels undergo fluctuations, but oxyHb or StO 2 undergo a characteristic early sharp rise, followed by a fall and another more persistent rise 3,6 . When irritants are used to induce skin erythema, vascular oxyHb levels directly correlate with the severity of the local erythema and inflammation 7 .…”

Fibrinogen-Related Proteins in Tissue Repair: How a Unique Domain with a Common Structure Controls Diverse Aspects of Wound Healing

“…75 Vasculotide also improved murine acute radiation skin damage, reducing inflammation and increasing endothelial cell density and survival. 76 Thus, studies focused on restoring the balance in the Tie2 signaling axis show beneficial effects for the treatment of diabetic wound healing and beyond.…”

Topical Treatment of Skin Injury Inflicted in Mice by X-Ray Irradiation

“…The total dose of 43 Gy was fractionated into 20 doses, beginning with milder doses, following the model of radiotherapy for cancer patients, and especially focusing on the sensitive case of breast cancer. Except the very specific type of athymic nude mice, previous studies reported the use of different types of hairy mice, such as C3n/HeN, BALB/c, and C57BLJ6, irradiating their flanks or hind legs by a single dose, such as 11, 15, 22, 30, 35, 44, 50, or 200 Gy [32, 39-43]. Using hairless mice, there is no need to shave the irradiated area, a factor which facilitates the repeated topical applications.…”