Liver-targeted doxorubicin: effects on rat regenerating hepatocytes.
OBJECTIVE
The conjugate of doxorubicin (DOXO) with lactosaminated human albumin (L-HSA) has the potential of improving DOXO efficacy in the treatment of hepatocellular carcinomas (HCCs) expressing the asialoglycoprotein receptor (ASGP-R). In view of an adjuvant chemotherapy with L-HSA-DOXO after the surgical removal of the tumour, in the present experiments we verified whether DOXO accumulation produced by the conjugate can impair the liver regeneration following hepatic resection in non-cirrhotic liver.


METHODS
Using saline-injected hepatectomised rats as controls, we studied the effects of the conjugate on the ultrastructure of regenerating hepatocytes and evaluated [3H]thymidine incorporation, mitotic index and rate of DNA recovery in the liver remnant.


RESULTS
L-HSA-DOXO caused a selective drug accumulation in liver remnant, with low DOXO levels in extra-hepatic tissues. It did not change the ultrastructure of hepatocytes and did not increase serum alanine aminotransferase. It decreased [3H]thymidine incorporation and mitotic index, causing a moderate delay in hepatic DNA recovery.


CONCLUSIONS
The experiments indicate a substantial resistance of rat regenerating hepatocytes to high intracellular concentrations of DOXO. They support the possibility of using L-HSA-DOXO in an adjuvant chemotherapy after the surgical removal of HCCs which maintain the ASGP-R.
Di Stefano
Giuseppina
G
Department of Experimental Pathology, University of Bologna, Via San Giacomo, Bologna, Italy.
Derenzini
Massimo
M
Kratz
Felix
F
Lanza
Marcella
M
Fiume
Luigi
L
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D004247:DNA / Q000302:isolation & purification; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004338:Drug Combinations; D004357:Drug Synergism; D006498:Hepatectomy; D022781:Hepatocytes / Q000502:physiology* / Q000648:ultrastructure; D006801:Humans; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D008940:Mitotic Index; D009994:Osmolar Concentration; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D004338:Drug Combinations; D012709:Serum Albumin; C046912:lactosaminated serum albumin; D004317:Doxorubicin; D004247:DNA; D000410:Alanine Transaminase; D013936:Thymidine