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Milk Growth Factors Enriched from Cheese Whey Ameliorate Intestinal Damage by Methotrexate When Administered Orally to Rats^1,2,

Gordon S. Howarth³, Geoffrey L. Francis^*, Johanna C. Cool, Xiaoning Xu, Roger W. Byard and Leanna C. Read

Cooperative Research Center for Tissue Growth and Repair and Child Health Research Institute, North Adelaide, South Australia 5006 ^* Commonwealth Scientific and Industrial Research Organization, Division of Human Nutrition, Adelaide, South Australia 5000 Women's and Children's Hospital, Department of Histopathology, North Adelaide, South Australia 5006, Australia

Currently, there are no truly effective therapies for the treatment of chemotherapy-induced intestinal mucositis, a debilitating side effect with a pathophysiology common to many chemotherapy regimens. We tested the efficacy of a growth factor extract derived from cheese whey against experimental intestinal mucositis in rats. Rats were subcutaneously injected with the chemotherapeutic drug methotrexate on d 1, 2 and 3 to induce severe damage in the small bowel and bacterial translocation across the gut. Whey extract (15 to 514 mg/d) was given orally for 5–12 d, starting on d 1. Controls were fed an isonitrogenous diet. Histological indices of villus and crypt integrity were utilized to assess potential efficacy of the extract. Administration of the whey extract for 5 d increased the villus surface length indices in the jejunum and ileum by 52% and 56%, respectively (P < 0.001) compared with controls not receiving the whey extract. The crypt area index was 64% greater (P < 0.001) in the jejunum, but not significantly greater in the duodenum or ileum compared with controls not receiving whey extract. Similarly, sucrase activity was significantly higher in the ileum (P < 0.001) but not significantly elevated in the jejunum, whereas bacterial translocation (incidence and number of colonies) was significantly reduced compared with controls not receiving whey extract. We conclude that oral whey growth factor extract reduces methotrexate-induced damage in the small bowel, which suggests clinical applications for the treatment of intestinal mucositis.

KEY WORDS: • milk • growth factors • methotrexate • mucositis • rats

¹ Supported by a Cooperative Research Centre grant from the Australian Federal Government and a grant from the Channel 7 Children's Research Foundation of South Australia Inc.

² 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 USC section 1734 solely to indicate this fact.

³ To whom correspondence and reprint requests should be addressed: Child Health Research Institute, 72 King William Road, North Adelaide, South Australia, Australia, 5006.

Manuscript received 19 February 1996. Revision accepted 11 June 1996.

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