Abstract
We investigated the potential dose related apoptotic effect of subchronic administration of the alkylating chemotherapeutic agent ifosfamide in different sites of the small and large rabbit intestine. Twenty New Zealand White rabbits received intravenously every week, for 10 weeks, 0 (group S, controls, n = 5), 30 (group A, n = 5), 45 (group B, n = 5) or 60 mg/kg ifosfamide (group C, n = 5). One day after the end of the treatment period, segments of jejunum, ileum, cecum, proximal and distal colon were excised. Intestinal mucosa apoptosis was detected by agarose gel electrophoresis and quantified by DNA fragmentation and standard terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick-end labelling (TUNEL) assays by which the percentage of fragmented DNA and the ratio of apoptotic cells per crypt (apoptotic index) were determined, respectively. At low dose (group A), ifosfamide had minor apoptotic effect on enterocytes, which was enhanced mainly in the small intestine when the dose was increased (group B); at the highest dose tested (group C), this effect was extended to the large intestine. In all groups of animals, the observed crypt cell apoptosis was maximal in the ileum, while minimal in the proximal colon. Our results show a dose and intestinal site-dependent induction of enterocyte apoptosis after subchronic ifosfamide administration in the rabbit.
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