Modulation of doxorubicin resistance in a doxorubicin-resistant human leukaemia cell by an immunoliposome targeting transferring receptor.
Using a doxorubicin-resistant subline (K562/ADM) of human leukaemia K562 cells (Tsuruo et al, 1986), the effect of immunoliposomes that targeted a cellular transferrin receptor (TFR) was examined by neutralization of doxorubicin (DOX) resistance. OKT9-CIL, prepared by conjugation of DOX-encapsulated liposome with an anti-TFR monoclonal antibody, OKT9 (Aisenberg and Wilkes, 1980), showed similar binding to both K562 and K562/ADM. Although an 80-fold higher sensitivity to free DOX on cell growth inhibition in K562 than in K562/ADM was found, the difference was clearly diminished after OKT9-CIL treatment through the increased sensitivity of K562/ADM. The cellular DOX level 30 min after the exposure of free DOX was 45-fold lower in K562/ADM than in K562, whereas nearly equivalent DOX levels were detected in K562 and K562/ADM after OKT9-CIL treatment. In addition, DOX in K562/ADM in the free DOX treatment was efficiently excreted by 54% within 120 min of incubation, whereas almost all DOX supplied by OKT9-CIL remained uncleared. Fluorescence microscopic observation showed that OKT9-CIL was internalized into juxtanuclear vesicles in K562/ADM cells. These results suggest that OKT9-CIL has a potency to accumulate DOX, resulting in augmentation of DOX cytotoxicity in DOX-resistant tumour cells.
Suzuki
S
S
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Tohoku University, Aobayama, Sendai, Japan.
Inoue
K
K
Hongoh
A
A
Hashimoto
Y
Y
Yamazoe
Y
Y
D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D002455:Cell Division / Q000187:drug effects; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D008081:Liposomes / Q000008:administration & dosage; D011990:Receptors, Transferrin / Q000276:immunology / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D008081:Liposomes; D011990:Receptors, Transferrin; D004317:Doxorubicin