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

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-alpha and assay of myeloperoxidase (MPO) activity, tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) 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-1 beta 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-1 beta 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. Conclusion These results suggest an important role of TNF-alpha, IL-1 beta and KC in the pathogenesis of intestinal mucositis induced by CPT-11.

Expression of vascular endothelian growth factor-C does not predict occult lymphnode metastasis in early oral squamous cell carcinoma

Strong vascular endothelial growth factor-C (VEGF-C) expression has been correlated to occurrence of lymph-node metastases in patients with oral squamous cell carcinoma (OSCC). The incidence of occult lymph-node metastasis remains a decisive factor in the prognosis of patients with early OSCC. The aim of this study was to evaluate VEGF-C expression as a predictor of occult lymph-node metastasis in OSCC. Eighty-seven patients with primary OSCC arising in the tongue or floor of mouth, clinically T1N0M0 or T2N0M0, with (pN+) and without (pN0) occult lymph-node metastases were analyzed for VEGF-C expression by malignant cells. Occult lymph-node metastases (pN+) were detected in 22% of the 64 patients who were submitted to elective neck dissection. No statistically significant difference was found between OSCC with and without occult lymph-node metastasis in regard to VEGF-C immunoexpression by malignant cells and clinicopathologic features. Independently of VEGF-C expression, lymph-node metastasis (PN+) was the most significant prognostic factor for overall survival of patients with OSCC (p = 0.030). These findings indicate that isolated VEGF-C expression by malignant cells is not of predictive value for occult lymph-node metastasis in the early stages of OSCC.