Enhanced uptake of lactosaminated human albumin by rat hepatocarcinomas: implications for an improved chemotherapy of primary liver tumors.
OBJECTIVE
The hepatocyte receptor for asialoglycoproteins (ASGP-R) internalizes macromolecules exposing galactosyl residues (MEGRs) which can be used as liver-addressed drug carriers. This receptor was also found on the cells of the large majority of well differentiated hepatocarcinomas (HCCs). The aim of the present experiments was to ascertain whether ASGP-R of HCCs is functionally active and these tumors can internalize higher quantities of MEGRs than extra-hepatic tissues.


METHODS
We injected radioactive lactosaminated human albumin (L-HSA) in rats with HCCs produced by nitroso-diethylamine and measured the radioactivity of tumors, surrounding liver, heart, intestine and kidney. L-HSA is a MEGR successfully used in humans as a hepatotropic drug carrier.


RESULTS
The levels of radioactivity of HCCs were two to three times lower than those of surrounding liver, but several times higher than those of extra-hepatic tissues. L-HSA accumulation in the tumors mainly occurred via the ASGP-R, as indicated by the 20 times lower penetration of non-lactosaminated HSA. L-HSA uptake by the well-differentiated tumors were four times higher compared with that by the poorly differentiated forms.


CONCLUSIONS
The present results suggest that in the chemotherapy of HCCs expressing the ASGP-R the extra-hepatic toxicity of anticancer agents can be reduced by conjugation to L-HSA.
Di Stefano
Giuseppina
G
Department of Experimental Pathology, University of Bologna, Italy.
Fiume
Luigi
L
Bolondi
Luigi
L
Lanza
Marcella
M
Pariali
Milena
M
Chieco
Pasquale
P
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D037263:Asialoglycoprotein Receptor / Q000378:metabolism; D002250:Carbon Radioisotopes; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004337:Drug Carriers; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D037263:Asialoglycoprotein Receptor; D002250:Carbon Radioisotopes; D004337:Drug Carriers; D012709:Serum Albumin; C046912:lactosaminated serum albumin