Circumvention of multidrug resistance and reduction of cardiotoxicity of doxorubicin in vivo by coupling it with low density lipoprotein.
Doxorubicin (Dox) was coupled into human low density lipoprotein (LDL) to form a complex LDL-Dox. In in vitro studies, the accumulation of LDL-Dox in human resistant hepatoma (R-HepG2) cells was found to be higher than that of free Dox in the cells, resulting in an increase of the cytotoxic effect on the cells. Moreover, in in vivo studies, under the same dosage of drugs (1 mg/kg), the anti-proliferative effect on the tumor cells of LDL-Dox in nude mice bearing R-HepG2 cells was higher than that of free Dox as evidenced by the larger reduction in tumor volumes and tumor weights in LDL-Dox treated group. Histological studies showed that LDL-Dox treatment did not cause any heart damage when compared with the control group. In contrast, Dox treatment caused disruption and vacuolization of myocardial filament. Plasma lactate dehydrogenase activity and plasma creatine kinase activity in nude mice bearing R-HepG2 cells were found to be elevated in the Dox-treated group but remained unchanged in LDL-Dox-treated group. The present studies indicate that when Dox is coupled with LDL, the multidrug resistance can be circumvented and the cardiotoxicity can be reduced.
Lo
Elka H K
EH
Department of Biochemistry, The Chinese University of Hong Kong, Shatin, N.T., China.
Ooi
Vincent E L
VE
Fung
K P
KP
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D004317:Doxorubicin / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D004337:Drug Carriers / Q000008:administration & dosage / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008077:Lipoproteins, LDL / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009206:Myocardium / Q000473:pathology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000097:blood / Q000188:drug therapy; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004337:Drug Carriers; D008077:Lipoproteins, LDL; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase