Protective Effect of Leuprorelin on Radiation-induced Intestinal Toxicity.

BACKGROUND/AIM - Patients with prostate cancer treated with neoadjuvant androgen ablation experience less radiation-induced intestinal toxicity, mostly due to a reduction of the volume of normal tissue exposed to high radiation doses. We aimed to evaluate if the anti-androgenic drug leuprorelin itself exerts a protective effect on irradiated bowel.

MATERIALS AND METHODS - Female, intact and castrated male C57BL/6J mice underwent 12-Gy total body irradiation, with or without a three-month leuprorelin (0.054 mg/kg/month i.p.) pre-treatment. After 24-72 h, mice were sacrificed and intestinal segments collected for histological, immunohistochemical and molecular analyses.

RESULTS - Leuprorelin markedly reduced radiation-induced jejunal and colonic histological alterations in mice, increased the number of regenerating crypts vs. irradiation, and reduced radiation-induced nitrotyrosine immunoreactivity. Leuprorelin significantly reduced radiation-induced matrix metallo-proteinase-2 (Mmp2) and -13, collagen 1 and -3, transforming growth factor-beta (Tgfb), p53, interleukin 6 (Il6), and B-cell lymphoma 2 (Bcl2)-associated X protein (Bax) gene expressions, and nuclear factor-kappa B (NFκB) and TGFβ protein expression, and hampered radiation-induced BCL2 protein down-regulation.

CONCLUSIONS - Leuprorelin protects mice from radiation-induced intestinal injury, likely through a reduction of tissue oxidative stress. These findings give a biological interpretation to clinical observations of improved intestinal tolerance in patients undergoing androgen ablation before RT.

Anticancer Res. 2015 Jul;35(7):3875-84.

Mangoni M1, Sottili M2, Gerini C2, Fucci R2, Pini A3, Calosi L3, Bonomo P2, Detti B2, Greto D2, Meattini I2, Simontacchi G2, Loi M2, Scartoni D2, Furfaro I2, Pallotta S4, Livi L2.

1 Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
2 Radiotherapy Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
3 Histology and Embryology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
4 Medical Physics Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.