Document Detail


Interleukin 15 offers selective protection from irinotecan-induced intestinal toxicity in a preclinical animal model.
MedLine Citation:
PMID:  9699654     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
S Cao; J D Black; A B Troutt; Y M Rustum
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  58     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  1998 Aug 
Date Detail:
Created Date:  1998-08-27     Completed Date:  1998-08-27     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  3270-4     Citation Subset:  IM    
Affiliation:
Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. scao@sc3101.med.buffalo.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents, Phytogenic / pharmacology,  toxicity*
Camptothecin / analogs & derivatives*,  pharmacology,  toxicity
Colon / drug effects,  pathology
Colorectal Neoplasms / drug therapy,  pathology
Diarrhea / chemically induced*,  prevention & control*
Disease Models, Animal
Drug Interactions
Duodenum / drug effects,  pathology
Female
Interleukin-15 / therapeutic use*
Intestinal Mucosa / drug effects,  pathology
Paraffin Embedding
Rats
Rats, Inbred F344
Grant Support
ID/Acronym/Agency:
CA16056/CA/NCI NIH HHS; R01 CA65761/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/Interleukin-15; 100286-90-6/irinotecan; 7689-03-4/Camptothecin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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