Mesna ameliorates intestinal mucosa damage after ifosfamide administration in the rabbit at a dose-related manner.
BACKGROUND
Cancer chemotherapy may lead to mucositis, a serious dose-limiting side effect. The alkylating agent ifosfamide is used in the treatment of various forms of cancer in combination with the uroprotective thiol mesna (2-mercaptoethane-sulfonate). The aims of this study were to assess the dose response intestinal mucosa damage of ifosfamide and to investigate the potential protective effect of mesna on rabbit intestinal epithelium.


METHODS
Fifty New Zealand White rabbits were randomly assigned to 10 groups of five animals each and received intravenously every week for 10 weeks either normal saline, ifosfamide, mesna, or ifosfamide plus mesna at three escalating dose levels (ifosfamide: 30, 45, or 60 mg/kg; mesna: 12, 18, or 24 mg/kg divided into two equal doses administered 4 h apart). Intestinal mucosa damage was assessed on the basis of crypt cell apoptosis and proliferation as well as intestinal morphometry. Apoptosis was detected by agarose gel electrophoresis and quantified by the DNA fragmentation assay and a standard terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) method by which the percentage of fragmented DNA and the apoptotic index were determined, respectively. The mitotic index and the crypt-villus (c/v) unit height were also measured in histological sections.


RESULTS
Ifosfamide caused a dose-related increase of crypt cell apoptosis and shortening of c/v unit, while it had a steady antimitotic effect. Mesna as a sole agent had no apoptotic or trophic effect on intestinal mucosa and hence no effect on intestinal morphometry. However, mesna, when administered concurrently with ifosfamide, ameliorated apoptosis, hypoproliferation, and mucosal atrophy at a dose-related manner.


CONCLUSIONS
Ifosfamide causes intestinal mucosa damage, which may be ameliorated in a dose-related manner by coadministration of mesna.
Laboratory of Experimental Surgery, School of Medicine, Democritus University of Thrace, 68 100 Alexandroupolis, Greece. pipsil@med.duth.gr
Petros
P
Ypsilantis
Ioannis
I
Tentes
Stelios F
SF
Assimakopoulos
Alexandros
A
Kortsaris
Chrisoula D
CD
Scopa
Constantinos
C
Simopoulos
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007069:Ifosfamide / Q000633:toxicity*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000473:pathology; D015080:Mesna / Q000494:pharmacology*; D011817:Rabbits
D015080:Mesna; D007069:Ifosfamide