Experimental model of hepatic venoocclusive disease (VOD) caused by dactinomycin--preliminary report about hepatoprotective effect of amifostine.
The purpose of the study was elaboration of the experimental model of hepatic venoocclusive disease (VOD) induced by dactinomycin and investigation of possible hepatoprotective effects of amifostine and heparin individually or in combination with dexamethasone. 198 Wistar strain male rats were used in the trial in two series of experiments. In the first series the experimental model of VOD induced by dactinomycin was elaborated on the group of 18 animals (divided into 3 groups receiving intraperitoneally isotonic salt solution, dactinomycin or nitrosamine). Nitrosamine--a well-known agent causing VOD--was used as positive control. Open biopsies of the liver and blood collections were repeated in order to determine liver enzymes' concentrations. Histopathological examinations demonstrated that dactinomycin caused liver lesion corresponding with VOD picture. Second series of animals was divided into 6 groups receiving the following drugs: I--0.9% NaCl solution, II--dactinomycin (ACT), III--ACT + fraxiparine s.c., IV--ACT + fraxiparine + dexamethasone, V--ACT + amifostine. Five animals from each group were sacrificed on the 3rd and 7th day after each cycle of drug administration. Blood was drawn in order to determine the following: AspAT, AlAT, Falk, GGTP and LDH. Intravital wedge biopsies under anesthesia with the use of inactin were also performed. Liver samples were stained with the use of H&E, p. a. S and Gomory's techniques. We did not find significant differences in liver enzymes' levels between the groups. Pathological changes corresponding with VOD picture of different intensification were found in liver samples from all the rats receiving ACT. Changes became more and more intensive after consecutive cycles. Lesion of central veins' and liver sinusoids' endothelium dominated. Fraxiparine administered individually or in combination with dexamethasone did not prevent the lesion. Administration of amifostine before ACT decreased pathomorphological changes in liver. Dactinomycin caused homogenous subclinical liver lesion corresponding with VOD. It may also occur in children receiving ACT in the course of nephroblastoma's treatment. But probably the changes are too subtle to manifest themselves clinically with exception of patients particularly sensitive (for example after previous radiotherapy). Lack of differences observed in liver enzymes' levels between the groups supports the explanation. Markers of lesion of liver vessels' endothelium should be looked for to make more specific diagnostics of VOD possible. Hepatoprotective properties of amifostine need further studies.


CONCLUSIONS
1. It is possible to create the experimental model of VOD induced by dactinomycin administration. 2. Amifostine seems to act hepatoprotectively to liver lesions caused by dactinomycin.
Czauderna
P
P
Department of Pediatric Surgery, Medical University, ul. Nowe Ogrody 1-6, 80-803 Gdańsk, Poland. czauderna@yoyo.pl
Chyczewski
L
L
Lech
K
K
Langner
G
G
Bednarczuk
G
G
Borowska
H
H
Arciszewska
E
E
D000410:Alanine Transaminase / Q000097:blood; D004999:Amifostine / Q000494:pharmacology*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D003609:Dactinomycin / Q000633:toxicity*; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D006503:Hepatic Veins / Q000187:drug effects / Q000473:pathology; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced* / Q000517:prevention & control*; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D017762:Nadroparin / Q000494:pharmacology; D009336:Necrosis; D009602:Nitrosamines / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar
D017762:Nadroparin; D009602:Nitrosamines; D003609:Dactinomycin; D003907:Dexamethasone; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D004999:Amifostine