[Intracellular distribution of bovine serum albumin-conjugated doxorubicin and multidrug resistance].
The intracellular distribution of bovine serum albumin (BSA)-conjugated [14C] doxorubicin (DXR) was investigated in a rat hepatoma cell line (AH66P) and its anthracycline resistant subline (AH66DR). After the conjugate had been taken up into the cells by endocytosis and degraded in the lysomes, active adducts with a molecular mass of approximately 2 kDa were distributed to target organellae such as nuclei and mitochondria. Drug accumulation in the nuclear fraction was lower in AH66DR cells than in AH66P cells, but the level of drug radioactivity in the DNA fraction, which was extracted from the same nuclear fraction, was higher in the AH66DR cells than in AH66P cells. It is presumed from these results that the intercalated level of the drug into DNA was sufficient to exhibit cytotoxicity against AH66DR cells as well as AH66P cells. A part of the active adducts was effluxed from AH66DR cells by P glycoprotein (Pgp) in the same manner as DXR because the efflux of the adducts was suppressed by verapamil, an inhibitor of Pgp. The IC50 values of BSA DXR conjugate was decreased from 120 nM to 2 nM for AH66DR cells and from 3 nM to 0.6 nM for AH66P cells by the co-treatment with 5/M verapamil, respectively.
Takahashi
N
N
Dept. of Biochemistry I, Jikei University School of Medicine.
Asakura
T
T
Ohkawa
K
K
Fukuda
K
K
Aoki
T
T
D000818:Animals; D002417:Cattle; D002467:Cell Nucleus / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004705:Endocytosis; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism; D015388:Organelles / Q000378:metabolism; D051381:Rats; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
D012710:Serum Albumin, Bovine; D004317:Doxorubicin; D014700:Verapamil