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Interleukin 15 Offers Selective Protection from Irinotecan-induced Intestinal Toxicity in a Preclinical Animal Model¹

Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263 [S. C., J. D. B., Y. M. R.]; and Immunex Corporation, Seattle, Washington 98101 [A. B. T.]

Irinotecan (CPT-11) is a chemotherapeutic agent that is active in the treatment of a variety of solid tumor malignancies. Diarrhea represents the most common dose-limiting toxicity that is independent of the schedule of administration. A rat model with dose-limiting toxicity profiles that are similar to those observed in patients treated with CPT-11 was developed and used to evaluate the role of interleukin 15 (IL-15) in the modulation of the therapeutic selectivity of CPT-11 in normal rats and rats bearing advanced colorectal cancer. The maximum tolerated dose and lethal dose (LD) of CPT-11 by i.v. push daily x 3 were 150 and 200 mg/kg/day, respectively. CPT-11 at the LD induced a 93–100% incidence of severe diarrhea and an 86–100% incidence of lethality in treated animals. IL-15, a cytokine with multiple mechanisms of action, was used at a 100 or 400 µg/kg/dose with different schedules of administration (3, 8, and 11 doses, i.p.) to protect against CPT-11-induced toxicity. IL-15 offered complete and sustained selective protection against CPT-11-induced delayed diarrhea and lethality. IL-15 also moderately potentiated the antitumor activity of CPT-11 in rats bearing advanced colorectal cancer. Morphological examination of rat intestinal tissues after treatment with LD of CPT-11 revealed dramatic protection of duodenal and colonic tissue architecture by IL-15. CPT-11 alone produced serious damage to duodenal villi and colonic crypts.

The results clearly demonstrated the ability of IL-15 to provide significant protection from CPT-11-induced intestinal toxicity with maintenance of antitumor activity, resulting in an increase in the therapeutic index of CPT-11. The clinical relevance of the results obtained in this model system needs to be confirmed.

¹ Supported in part by Interactive Grant RO1 CA65761 and Institute Core Grant CA16056 from the National Cancer Institute and by Immunex Corporation.

² To whom requests for reprints should be addressed, at Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: (716) 845-3394; Fax: (716) 845-8857; E-mail: scao@sc3101.med.buffalo.edu.

Received 5/ 4/98. Accepted 6/16/98.

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