INTERLEUKIN-15 OFFERS SELECTIVE PROTECTION FROM IRINOTECAN-INDUCED INTESTINAL TOXICITY IN A PRECLINICAL ANIMAL-MODEL

Irinotecan (CPT-11) is a chemotherapeutic agent that is active in the treatment of a variety of solid tumor malignancies. Diarrhea represent s the most common dose-limiting toxicity that is independent of the sc hedule of administration. A rat model with dose-limiting toxicity prof iles that are similar to those observed in patients treated with CPT-1 1 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 tolera ted dose and lethal dose (LD) of CPT-11 by i.v. push daily x 3 were 15 0 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 mu g/kg/dose with different schedules of adm inistration (3, 8, and 11 doses, i.p.) to protect against CPT-11-induc ed toxicity. IL-15 offered complete and sustained selective protection against CPT-11-induced delayed diarrhea and lethality, IL-15 also mod erately potentiated the antitumor activity of CPT-11 in rats hearing a dvanced colorectal cancer. Morphological examination of rat intestinal tissues after treatment with LD of CPT-11 revealed dramatic protectio n of duodenal and colonic tissue architecture by IL-15, CPT-11 alone p roduced serious damage to duodenal villi and colonic crypts. The resul ts clearly demonstrated the ability of IL-15 to provide significant pr otection from CPT-11-induced intestinal toxicity with maintenance of a ntitumor activity, resulting in an increase in the therapeutic index o f CPT-11, The clinical relevance of the results obtained in this model system needs to be confirmed.