The antitumor activity of a lactosaminated albumin conjugate of doxorubicin in a chemically induced hepatocellular carcinoma rat model compared to sorafenib.
BACKGROUND
Worldwide, consistent survival benefit for chemotherapy in hepatocellular carcinoma (HCC) is a golden goal for concerned researchers. Nexavar®(sorafenib) is the only approved agent that achieved touchable successes in this regard. Thus, there is a pressing medical need for new promising drugs to improve HCC therapy.


OBJECTIVE
our designed lactosaminated albumin conjugate of doxorubicin (L-HSA-DOXO) that rapidly and preferentially accumulates in the liver is compared, for the first time at its MTD, with doxorubicin and sorafenib, not only for antitumor efficacy but also for overall survival.


METHODS
HCC was induced in male Wistar rats with N-nitrosodiethylamine added to drinking water (100mg/L) for 8 weeks. Endpoints were antitumor efficacy, tolerability and overall survival.


RESULTS
L-HSA-DOXO proved to be superior at least over doxorubicin in the majority of assessed endpoints. Circulating AFP-L3% was diminished in L-HSA-DOXO (14.5%) and sorafenib (18.4%) groups compared to DENA (31.1%) and doxorubicin (29.5%) groups. This superiority was further confirmed by Western blot analyses of some novel HCC biomarkers. Survival study reinforced consistent benefits of both L-HSA-DOXO and sorafenib.


CONCLUSIONS
L-HSA-DOXO shows at least comparable activity to sorafenib which clinically achieves only ∼3 months overall survival benefit. Combination of these two agents could act beneficially or synergistically via two different modes of action to fight HCC.
Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, Egypt. Electronic address: b_elkot@yahoo.com.
Bakheet
B
Elsadek
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt.
Ahmed
A
Mansour
Department of Biochemistry, Faculty of Medicine, Assiut University, Assiut, Egypt.
Tahia
T
Saleem
Tumor Biology Center, Division of Macromolecular Prodrugs, Freiburg, Germany(1).
André
A
Warnecke
Tumor Biology Center, Division of Macromolecular Prodrugs, Freiburg, Germany(1).
Felix
F
Kratz
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality; D004052:Diethylnitrosamine; D004317:Doxorubicin / Q000627:therapeutic use*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin; D000077157:Sorafenib; D015996:Survival Rate
D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; D010671:Phenylurea Compounds; D012709:Serum Albumin; D009536:Niacinamide; D004052:Diethylnitrosamine; D004317:Doxorubicin; D000077157:Sorafenib
Drug targeting; Human serum albumin; Prodrug