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 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 microg/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.
Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. scao@sc3101.med.buffalo.edu
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D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000633:toxicity*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D003106:Colon / Q000187:drug effects / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced* / Q000517:prevention & control*; D004195:Disease Models, Animal; D004347:Drug Interactions; D004386:Duodenum / Q000187:drug effects / Q000473:pathology; D005260:Female; D019409:Interleukin-15 / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D000077146:Irinotecan; D016612:Paraffin Embedding; D051381:Rats; D011916:Rats, Inbred F344
D000972:Antineoplastic Agents, Phytogenic; D019409:Interleukin-15; D000077146:Irinotecan; D002166:Camptothecin