Effect and risk of AEE788, a dual tyrosine kinase inhibitor, on regeneration in a rat liver resection model.
BACKGROUND
AEE788, a dual tyrosine kinase inhibitor, has antiproliferative effects on diverse tumor models in mice. We aimed to investigate whether AEE788 blocks liver regeneration and causes drug-related side effects.


METHODS
Rats treated orally with 50 mg/kg AEE788 or solvent every 2 days were subjected to 70% partial hepatectomy (PH) and sacrificed on postoperative days 1, 2, 7, and 28. Liver regeneration was evaluated using liver weight to body weight ratio, BrdU-staining, mitotic index, and PCR for PCNA (proliferating cell nuclear antigen). Side effects on the gastrointestinal system and liver were assessed using clinical chemistry, histology, silver staining, and immunohistochemistry. Plasma and liver tissue levels of AEE788 were measured using spectrometry.


RESULTS
AEE788 treatment did not inhibit liver regeneration. No obvious drug-related systemic or hepatic side effects were observed. Restoration of liver architecture during liver regeneration was not obviously impaired, even after 4 weeks' AEE788 treatment. After a 1-week treatment, AEE788 concentrations in plasma and liver tissue in the PH group were 3-fold and 8-fold higher than the non-PH group, respectively.


CONCLUSIONS
Its antiproliferative properties, good tolerance, and lack of inhibition on liver regeneration make AEE788 a potential candidate for clinical study with oncological PH, but one that carries the risk of overexposure in the early postoperative phase.
Deng
M
M
Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Hufelandstrasse 55, Essen, Germany.
Huang
H
H
Dirsch
O
O
Dahmen
U
U
D000818:Animals; D001835:Body Weight; D002455:Cell Division / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000150:complications; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006498:Hepatectomy; D007275:Injections, Intravenous; D008113:Liver Neoplasms / Q000556:secondary / Q000601:surgery*; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D051379:Mice; D008940:Mitotic Index; D009362:Neoplasm Metastasis; D009929:Organ Size; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors
D011687:Purines; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; C489254:AEE 788