Cancer Chemother Pharmacol DOI 10.1007/s00280-008-0715-9 123 ORIGINAL ARTICLE Gastrointestinal dysmotility in 5-Xuorouracil-induced intestinal mucositis outlasts inXammatory process resolution Pedro M. G. Soares · José Maurício S. C. Mota · Antoniella S. Gomes · Ricardo B. Oliveira · Ana Maria S. Assreuy · Gerly Anne C. Brito · Armênio A. Santos · Ronaldo A. Ribeiro · Marcellus H. L. P. Souza Received: 20 December 2007 / Accepted: 17 February 2008 © Springer-Verlag 2008 Abstract Aim To evaluate gastrointestinal motility during 5-Xuoro- uracil (5-FU)-induced intestinal mucositis. Materials and methods Wistar rats received 5-FU (150 mg kg ¡1 , i.p.) or saline. After the 1st, 3rd, 5th, 15th and 30th day, sections of duodenum, jejunum and ileum were removed for assessment of epithelial damage, apopto- tic and mitotic indexes, MPO activity and GSH concentra- tion. In order to study gastrointestinal motility, on the 3rd or 15th day after 5-FU treatment, gastric emptying in vivo was measured by scintilographic method, and stomach or duodenal smooth muscle contractions induced by CCh were evaluated in vitro. Results On the third day of treatment, 5-FU induced a sig- niWcant villi shortening, an increase in crypt depth and intestinal MPO activity and a decrease in villus/crypt ratio and GSH concentration. On the Wrst day after 5-FU there was an increase in the apoptosis index and a decrease in the mitosis index in all intestinal segments. After the 15th day of 5-FU treatment, a complete reversion of all these param- eters was observed. There was a delay in gastric emptying in vivo and a signiWcant increase in gastric fundus and duo- denum smooth muscle contraction, after both the 3rd and 15th day. Conclusion 5-FU-induced gastrointestinal dysmotility outlasts intestinal mucositis. Keywords 5-Fluorouracil · Gastric emptying · Mucositis · Smooth muscle contractility Introduction Cancer chemotherapy-associated dyspepsia syndrome (CADS) is one of the most important causes of chemother- apy-related cancer morbidity [10, 20] but its pathophysio- logical mechanisms are still not fully established [17]. Gastrointestinal dysmotility-related symptoms such as early satiety, anorexia, nausea and vomiting have been associated with delayed gastric emptying [17]. The antimetabolite agent 5-Xuorouracil (5-FU) has been used in the treatment of a range of cancers, including colo- rectal and breast cancers [18, 34] and can induce intestinal damage, referred as intestinal mucositis [4]. Duncan and Grant [13] proposed that intestinal mucositis is developed through three interlinked stages of increasing epithelial dysfunction: the initial inXammatory phase, the epithelial degradation phase, and the ulceration/bacterial phase. Sub- sequently, there is a re-establishment of functional epithelia [29, 40]. Intestinal inXammation is associated with gastrointesti- nal dysmotility, not only at the site of inXammation, but also at distant non-inXamed sites [1, 3, 21, 22]. A number of inXammatory mediators have been implicated both in acute and long-lasting alterations of smooth muscle con- tractility induced by intestinal inXammation [9]. Recently, P. M. G. Soares · J. M. S. C. Mota · A. S. Gomes · G. A. C. Brito · A. A. Santos · R. A. Ribeiro · M. H. L. P. Souza (&) Centro de Biomedicina, Faculdade de Medicina, Universidade Federal do Ceará, Rua Cel. Nunes de Melo, 1315, Rodolfo TeóWlo, Fortaleza-CE 60.430-270, Brazil e-mail: souzamar@ufc.br R. B. Oliveira Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil A. M. S. Assreuy Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza-CE, Brazil