Role of cytokines (TNF-α, IL-1β and KC) in the pathogenesis of CPT-11-induced intestinal mucositis in mice: effect of pentoxifylline and thalidomide

• Published in: Cancer chemotherapy and pharmacology 2008-04, Vol.61 (5), p.775-784
• Main Authors: Melo, Maria Luisa P., Brito, Gerly A. C., Soares, Rudy C., Carvalho, Sarah B. L. M., Silva, Johan V., Soares, Pedro M. G., Vale, Mariana L., Souza, Marcellus H. L. P., Cunha, Fernando Q., Ribeiro, Ronaldo A.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents, Phytogenic - adverse effects; Biological and medical sciences; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Cancer Research; Chemokines - adverse effects; Chemokines - metabolism; Diarrhea - drug therapy; Diarrhea - etiology; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Injections, Intraperitoneal; Interleukin-1beta - drug effects; Interleukin-1beta - metabolism; Intestine, Small - pathology; Male; Medical sciences; Medicine; Medicine & Public Health; Mice; Mucositis - chemically induced; Mucositis - drug therapy; Oncology; Original Article; Pentoxifylline - pharmacology; Peroxidase - drug effects; Peroxidase - metabolism; Pharmacology. Drug treatments; Pharmacology/Toxicology; Thalidomide - pharmacology; Tumor Necrosis Factor-alpha - drug effects; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-007-0534-4

Introduction Irinotecan (CPT-11) is an inhibitor of DNA topoisomerase I and is clinically effective against several cancers. A major toxic effect of CPT-11 is delayed diarrhea; however, the exact mechanism by which the drug induces diarrhea has not been established. Purpose Elucidate the mechanisms of induction of delayed diarrhea and determine the effects of the cytokine production inhibitor pentoxifylline (PTX) and thalidomide (TLD) in the experimental model of intestinal mucositis, induced by CPT-11. Materials and methods Intestinal mucositis was induced in male Swiss mice by intraperitoneal administration of CPT-11 (75 mg/kg) daily for 4 days. Animals received subcutaneous PTX (1.7, 5 and 15 mg/kg) or TLD (15, 30, 60 mg/kg) or 0.5 ml of saline daily for 5 and 7 days, starting 1 day before the first CPT-11 injection. The incidence of delayed diarrhea was monitored by scores and the animals were sacrificed on the 5th and 7th experimental day for histological analysis, immunohistochemistry for TNF-α and assay of myeloperoxidase (MPO) activity, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and KC ELISA. Results CPT-11 caused significant diarrhea, histopathological alterations (inflammatory cell infiltration, loss of crypt architecture and villus shortening) and increased intestinal tissue MPO activity, TNF-α, IL-1β and KC level and TNF-α immuno-staining. PTX inhibited delayed diarrhea of mice submitted to intestinal mucositis and reduced histopathological damage, intestinal MPO activity, tissue level of TNF-α, IL-1β and KC and TNF-α immuno-staining. TLD significantly reduced the lesions induced by CPT-11 in intestinal mucosa, decreased MPO activity, TNF-α tissue level and TNF-α immuno-staining, but did not reduce the severity of diarrhea. Conclusion These results suggest an important role of TNF-α, IL-1β and KC in the pathogenesis of intestinal mucositis induced by CPT-11.