Abstract
PURPOSE: To evaluate the ability of D-saccharic acid 1.4-lactone (SAL), a beta-glucuronidase inhibitor, to prevent irinotecan hydrochloride (CPT-11) from inducing mucosal damage as a cause of diarrhea in rats. METHODS: Wistar rats were divided into six groups of three animals each, administered 1.0 ml isotonic solution intraperitoneally once daily for up to three consecutive days, respectively for up to six days. The series were as follows: (1) On days 1-3: saline; (2) On days 1-3: 200 mg CPT-11/m2; (3) On days -3 to -1 relative to the first administration of CPT-11: 10 mg/ml SAL; on days 1-3: 200 mg CPT-11/m2; (4) On days -3 to +3 relative to the first administration of CPT-11: 10 mg/ml SAL, and on days 1-3: additional 200 mg CPT-11/m2; (5) On days 1-3: 200 mg CPT-11/m2 (0.5 ml) + 10 mg/0.5 ml SAL; (6) On days -3 to -1 relative to the first administration of CPT-11: 3 mg/ml SAL, and on days 1-3: 200 mg CPT-11/m2. Luminal mucosa damage of the small intestine was detected by histology 24 h after the last intraperitoneal application. Peptidase activities of the proximal jejunum were measured by using an in situ perfusion model. RESULTS: Following intraperitoneal CPT-11 treatment, using conventional histology of paraffin sections, we observed severe mucosal damage. This was reflected by a decrease of the villi/crypt ratio, an increase of apoptotic cells, as well as an increase of mitotic figures in the crypt region. There was a concomitant increased lymphatic infiltration in mucosa of CPT-11 treated rats. This damage pattern could be clearly reduced by co-treatment with the beta-glucuronidase inhibitor, SAL, independent of the treatment schedule. In contrast to our expectations based on previous reports, the intraperitoneal application of CPT-11 alone or in combination with SAL did not cause significant differences in luminal enzyme liberation in comparison with controls in the in situ perfusion assay. CONCLUSIONS: The beta-glucuronidase inhibitor SAL is able to significantly reduce CPT-11-induced mucosal damage in the small intestine of rats. This observation might soon have a clinical impact for the treatment of patients with CPT-11.