Cytotoxic effect of the protein-doxorubicin conjugates on the multidrug-resistant human myelogenous leukemia cell line, K562, in vitro.
In vitro studies were performed to examine the antitumor effect of protein-doxorubicin (DXR) conjugate on the growth of the multidrug-resistant human chronic myelogenous leukemia cell line, K562/DXR. The 50% inhibitory concentration (IC50) for DXR in the K562/DXR cell line was 20 nM (in the K562 parental cell line, IC50 was 3.2 nM). Treatment of both types of cells with various concentrations of DXR or conjugates at equivalent concentrations of DXR was carried out. One type of the conjugates used was human serum albumin (HSA)-DXR conjugate and human transferrin (Tf)-DXR conjugate via a glutaraldehyde bridge (HSA-ga-DXR, Tf-ga-DXR, respectively) and another type used was HSA-DXR conjugate with a dextran bridge (HSA-dex-DXR). All of these conjugates showed potent dose-dependent inhibition of cell growth against the K562/DXR cells as compared with the cells treated with DXR or other controls. IC50 for HSA-ga-DXR, Tf-ga-DXR and HSA-dex-DXR conjugates in the K562/DXR cell line was 2.4, 3.6 and 1.0 (equivalent DXR) nM, respectively, which were approximately similar to the value of the K562 treated with DXR. Through the treatment of K562/DXR cells with HSA-DXR conjugate, the intracellular drug concentration increased as a function of time up to 24 h compared with the cells treated with DXR. Intracellular DXR effluxed rapidly from K562/DXR cells, but HSA-ga-DXR as well as HSA-dex-DXR conjugates remained in the cells at a relatively high concentration for a long time. These results indicate that it may be possible to overcome multidrug resistance by chemically modifying DXR, such as by conjugation of the drug with proteins.
Hatano
T
T
Department of Biochemistry, Jikei University School of Medicine, Tokyo, Japan.
Ohkawa
K
K
Matsuda
M
M
D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004351:Drug Resistance; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism; D012709:Serum Albumin / Q000737:chemistry; D014168:Transferrin / Q000737:chemistry; D014407:Tumor Cells, Cultured
D012709:Serum Albumin; D014168:Transferrin; D004317:Doxorubicin