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Keratinocyte Growth Factor Protects Mice from Chemotherapy and Radiation-induced Gastrointestinal Injury and Mortality¹

Amgen Center, Thousand Oaks, California 91320-1789 [C. L. F., J. V. B., K. L. R., J. N. C., C. R. D., K. L. W., S. Y., D. C. H., B. W., C. O. S., A. M. H., Z-N. L., S. L. A., G. F. P., A. T., T. R. U., D. L. L.], and Christine CRC Research Centre, Patterson Institute for Cancer Research, Manchester M20 9BX, United Kingdom [C. S. P.]

Keratinocyte growth factor (KGF) stimulates the proliferation and differentiation of epithelial cells including those of the gastrointestinal tract. Although chemotherapeutics and radiation exposure kill rapidly proliferating tumor cells, rapidly dividing normal cells of the host's gastrointestinal tract are also frequently damaged, leading to the clinical condition broadly termed "mucositis." In this report, recombinant human KGF used as a pretreatment in several mouse models of chemotherapy and/or radiation-induced gastrointestinal injury significantly improved mouse survival. Using multiple-dose 5-fluorouracil, methotrexate, and radiation in combination and total body radiation alone models, KGF increased survival by 55% or greater. In the models that used chemotherapy with or without radiation, KGF significantly ameliorated weight loss after injury and accelerated weight gain during recovery. The basis of these systemic benefits appears to be due in part to the trophic effects of the growth factor on the intestinal epithelium because KGF pretreatment caused an increase in measures of mucosal thickness (villus height and crypt depth) that persisted during the course of 5-fluorouracil chemotherapy. Treatment with KGF also afforded a 3.5-fold improvement in crypt survival in the small intestine, suggesting that KGF also has a direct effect on the crypt stem cells. These data indicate that KGF may be therapeutically useful to lessen the intestinal side effects of current cancer therapy regimens.

¹ The work of C. S. P. was funded by the Cancer Research Campaign.

² To whom requests for reprints should be addressed, at Amgen, Inc., 1840 DeHavilland Drive, Thousand Oaks, CA 91320-1789.

³ Present address: Prizm Pharmaceuticals, San Diego, CA 92121.

Received 7/29/97. Accepted 12/31/97.

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