# Investigation of Gastrointestinal Toxicities Associated with Concurrent Abdominal Radiation Therapy and the Tyrosine Kinase Inhibitor Sunitinib in a Mouse Model

## TL;DR

This study investigates how combining radiation therapy with the drug sunitinib affects the gastrointestinal health of mice, finding increased toxicity and reduced healing.

## Contribution

The study reveals that sunitinib combined with abdominal radiation therapy impairs intestinal healing in mice due to reduced angiogenic response.

## Key findings

- Mice receiving RT + sunitinib experienced greater weight loss compared to those receiving RT alone.
- Irradiated groups showed significant increases in inflammation.
- RT alone had higher CD31+ cell density compared to sunitinib alone, indicating reduced vascular response with combined treatment.

## Abstract

Tyrosine kinase inhibitors (TKIs) may be combined with radiation therapy (RT) to enhance tumor control; however, increased incidences of gastrointestinal (GI) toxicity have been reported with this combination. We hypothesize that toxicity is due to compromised intestinal healing caused by inhibition of vascular repair and proliferation pathways. This study explores underlying tissue toxicity associated with abdominal RT and concurrent sunitinib in a mouse model. Four groups of CD-1 mice were treated with 12 Gy abdominal RT, oral sunitinib, abdominal RT + sunitinib, or sham treatment. Mice received oral sunitinib or the vehicle via gavage for 14 days. On day 7, mice were irradiated with 12 Gy abdominal RT or sham treated. Mice were euthanized on day 14 and intestinal tract was harvested for semiquantitative histopathologic evaluation and immunohistochemical quantification of proliferation (Ki67) and vascular density (CD31). Non-irradiated groups had stable weights while abdominal irradiation resulted in weight loss, with mice receiving RT + SUN having greater weight loss than mice receiving RT alone. Semiquantitative analysis showed significant increases in inflammation in irradiated groups. The difference in the density of CD31+ cells was significantly increased in RT alone compared to SUN alone. Ki67+ density was not significant. In summary, we identify a lack of angiogenic response in irradiated GI tissues when abdominal RT is combined with a TKI, which may correlate with clinical toxicities seen in canine and human patients receiving combined treatment.