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


OBJECTIVE
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.


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-alpha and assay of myeloperoxidase (MPO) activity, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) 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-alpha, IL-1beta and KC level and TNF-alpha immuno-staining. PTX inhibited delayed diarrhea of mice submitted to intestinal mucositis and reduced histopathological damage, intestinal MPO activity, tissue level of TNF-alpha, IL-1beta and KC and TNF-alpha immuno-staining. TLD significantly reduced the lesions induced by CPT-11 in intestinal mucosa, decreased MPO activity, TNF-alpha tissue level and TNF-alpha immuno-staining, but did not reduce the severity of diarrhea.


CONCLUSIONS
These results suggest an important role of TNF-alpha, IL-1beta and KC in the pathogenesis of intestinal mucositis induced by CPT-11.
Melo
Maria Luisa P
ML
Department of Physiology, Faculty of Medicine, Federal University of Ceará, Rua Cel. Nunes de Melo, 1127, CEP 60.430-270 Fortaleza, CE, Brazil.
Brito
Gerly A C
GA
Soares
Rudy C
RC
Carvalho
Sarah B L M
SB
Silva
Johan V
JV
Soares
Pedro M G
PM
Vale
Mariana L
ML
Souza
Marcellus H L P
MH
Cunha
Fernando Q
FQ
Ribeiro
Ronaldo A
RA
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives*; D018925:Chemokines / Q000009:adverse effects / Q000378:metabolism; D003967:Diarrhea / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007274:Injections, Intraperitoneal; D053583:Interleukin-1beta / Q000187:drug effects / Q000378:metabolism; D007421:Intestine, Small / Q000473:pathology; D000077146:Irinotecan; D008297:Male; D051379:Mice; D052016:Mucositis / Q000139:chemically induced* / Q000188:drug therapy; D010431:Pentoxifylline / Q000494:pharmacology*; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D013792:Thalidomide / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D018925:Chemokines; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; C074302:keratinocyte-derived chemokines; D013792:Thalidomide; D000077146:Irinotecan; D009195:Peroxidase; D010431:Pentoxifylline; D002166:Camptothecin