Anticancer research · 2015
Protective Effect of Leuprorelin on Radiation-induced Intestinal Toxicity.
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Mangoni Monica, Sottili Mariangela, Gerini Chiara, Fucci Rossella, Pini Alessandro, Calosi Laura, Bonomo Pierluigi, Detti Beatrice, Greto Daniela, Meattini Icro, Simontacchi Gabriele, Loi Mauro, Scartoni Daniele, Furfaro Ilaria, Pallotta Stefania, Livi Lorenzo
Аннотация
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.
CONCLUSION: 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.
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.
CONCLUSION: 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.