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Research Articles

A novel animal model to investigate fractionated radiotherapy-induced alimentary mucositis: the role of apoptosis, p53, nuclear factor-B, COX-1, and COX-2

Departments of ¹ Medical Oncology and ² Radiation Oncology, Royal Adelaide Hospital; ³ Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia

Requests for reprints: Ann S.J. Yeoh, Mucositis Research Group, Dame Roma Mitchell Cancer Research Laboratory, Level 4, Hanson Institute, Frome Road, Adelaide, South Australia 5000, Australia. Phone: 61-8-8222-3547; Fax: 61-8-8222-3217. E-mail: ann.yeoh{at}imvs.sa.gov.au

Abstract

Radiation-induced mucositis is a common and serious side effect of radiotherapy. Molecular mechanisms of mucosal injury, however, are still poorly understood and extremely difficult to study in humans. A novel Dark Agouti rat model using fractionated radiotherapy to induce mucositis has been developed to investigate the occurrence of alimentary mucosal injury. Twenty-four Dark Agouti rats were randomly assigned to receive either fractionated radiotherapy or no radiotherapy. The irradiated rats received a fractionated course of abdominal radiotherapy at 45 Gy/18 fractions/6 weeks treating thrice weekly (i.e., at a radiation dose of 2.5 Gy per fraction). After each week of radiation, a group of irradiated rats was killed. Histomorphology and mucin distribution in the alimentary tract was investigated. The terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling assay was used to examine apoptosis in the colon and jejunum, and intestinal morphometry was used to assess villus length, crypt length, and mitotic crypt count. Immunohistochemistry of p53, nuclear factor-B, cyclooxygenase (COX)-1, and COX-2 was also done. The fractionated radiotherapy course induced alimentary mucositis from week 1, with more severe injury seen in the small intestine. The hallmark appearance of apoptosis was present in the crypts of the small and large intestine. In the jejunum and colon, goblet cell disorganization and degeneration was obvious and crypt mitotic counts were severely depleted throughout the treatment. Expression of p53, nuclear factor-B, COX-1, and COX-2 was increased in the irradiated intestinal sections. Fractionated radiation-induced alimentary mucositis has been effectively documented in the Dark Agouti rat for the first time. Further studies investigating the molecular mechanisms underlying radiation-induced mucositis are planned to ultimately achieve anti–mucotoxic-targeted therapies. [Mol Cancer Ther 2007;6(8):2319–27]

Grant support: Conservation Council of South Australia fellowship (R.J. Gibson).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 2/19/07; revised 5/17/07; accepted 6/29/07.