Bovine serum albumin-doxorubicin conjugate overcomes multidrug resistance in a rat hepatoma.
A bovine serum albumin-conjugated doxorubicin via the glutaraldehyde bridge (BSA-DXR conjugate) showed potent dose-dependent inhibition of cell growth against daunorubicin-resistant AH66 (AH66DR) cells as well as parental AH66 (AH66P) cells in vitro as compared to treatment with DXR or BSA-glutaraldehyde conjugate without DXR (BSA-GA). In the culture of AH66DR with BSA-DXR conjugate, drug accumulation in the AH66DR cells increased as a function of time up to 24 h reaching approximately the same drug level as AH66P cells treated with DXR. The intracellular accumulation of the BSA-DXR conjugate was inhibited by the addition of ammonium chloride, while that of DXR alone was not inhibited. Intracellular DXR was effluxed rapidly from AH66DR cells, but BSA-DXR conjugate or pharmacologically active DXR adduct remained in the cells at a relatively high concentration over a 36-h time period. The life-prolonging effect of the conjugate was assessed using rats inoculated i.p. with AH66P or AH66DR. The rats were treated with the BSA-DXR conjugate, DXR, a mixture of DXR with BSA, or BSA-GA by either the i.p. or i.v. route. Treatment with DXR had no significant surviving effect as compared to that with saline in AH66P-bearing rats. By contrast, BSA-DXR conjugate showed a significant life-prolonging effect as compared with DXR alone in the same degree both in AH66P- and AH66DR-bearing rats. BSA-GA did not show any toxicity in vivo as well as in vitro. These results indicate that the BSA-DXR conjugate allows DXR to escape from the multidrug resistance mechanism.
Ohkawa
K
K
Department of Biochemistry, Jikei University School of Medicine, Tokyo, Japan.
Hatano
T
T
Yamada
K
K
Joh
K
K
Takada
K
K
Tsukada
Y
Y
Matsuda
M
M
D000818:Animals; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D004351:Drug Resistance; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D012710:Serum Albumin, Bovine / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C069982:doxorubicin-BSA conjugate; D012710:Serum Albumin, Bovine; D004317:Doxorubicin