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01 January 2000

Experimental model of hepatic venoocclusive disease (VOD) caused by dactinomycin--preliminaryreport about hepatoprotective effect of amifostine.

Piotr Czauderna, Lech Chyczewski, Katarzyna Lech, Gabriela Langner, Gabriela Bednarczuk, Halina Borowska, Ewa Arciszewska

Med Sci Monit 2000; 6(3): SR446-453 :: ID: 421327

Abstract

The purpose of the study was elaboration of the experimental model of hepaticvenoocclusive disease (VOD) induced by dactinomycin and investigation of possible hepatoprotective effectsof amifostine and heparin individually or in combination with dexamethasone. 198 Wistar strain male ratswere used in the trial in two series of experiments. In the first series the experimental model of VODinduced by dactinomycin was elaborated on the group of 18 animals (divided into 3 groups receiving intraperitoneallyisotonic salt solution, dactinomycin or nitrosamine). Nitrosamine--a well-known agent causing VOD--wasused as positive control. Open biopsies of the liver and blood collections were repeated in order todetermine liver enzymes' concentrations. Histopathological examinations demonstrated that dactinomycincaused liver lesion corresponding with VOD picture. Second series of animals was divided into 6 groupsreceiving the following drugs: I--0.9% NaCl solution, II--dactinomycin (ACT), III--ACT + fraxiparines.c., IV--ACT + fraxiparine + dexamethasone, V--ACT + amifostine. Five animals from each group were sacrificedon the 3rd and 7th day after each cycle of drug administration. Blood was drawn in order to determinethe following: AspAT, AlAT, Falk, GGTP and LDH. Intravital wedge biopsies under anesthesia with the useof inactin were also performed. Liver samples were stained with the use of H&E, p. a. S and Gomory'stechniques. We did not find significant differences in liver enzymes' levels between the groups. Pathologicalchanges corresponding with VOD picture of different intensification were found in liver samples fromall the rats receiving ACT. Changes became more and more intensive after consecutive cycles. Lesion ofcentral veins' and liver sinusoids' endothelium dominated. Fraxiparine administered individually or incombination with dexamethasone did not prevent the lesion. Administration of amifostine before ACT decreasedpathomorphological changes in liver. Dactinomycin caused homogenous subclinical liver lesion correspondingwith VOD. It may also occur in children receiving ACT in the course of nephroblastoma's treatment. Butprobably the changes are too subtle to manifest themselves clinically with exception of patients particularlysensitive (for example after previous radiotherapy). Lack of differences observed in liver enzymes' levelsbetween the groups supports the explanation. Markers of lesion of liver vessels' endothelium should belooked for to make more specific diagnostics of VOD possible. Hepatoprotective properties of amifostineneed further studies. CONCLUSIONS: 1. It is possible to create the experimental model of VOD inducedby dactinomycin administration. 2. Amifostine seems to act hepatoprotectively to liver lesions causedby dactinomycin.

Keywords: Alanine Transaminase, amifostine, Aspartate Aminotransferases, Dactinomycin, Dexamethasone, Hepatic Veins, Hepatic Veno-Occlusive Disease, Hepatocytes, Liver, nadroparin, Necrosis, Nitrosamines, Rats, Wistar

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750