Cytotoxicity of anti-c-erbB-2 immunoliposomes containing doxorubicin on human cancer cells.
We have examined the selective cytotoxicity of immunoliposomes containing doxorubicin (chemoimmunoliposomes, CILs) targeting the c-erbB-2 gene product (gp185) or gp125. Anti-gp185 and anti-gp125 CILs were prepared by conjugation of doxorubicin-containing liposomes with monoclonal antibodies SER4 (IgG) and HBJ127 (IgG) respectively. Both CILs bound to human SKBr-3 breast cancer cells and MKN-7 human gastric cancer cells, which express both antigens in high density. The IC50 of anti-gp185 CILs on protein synthesis by SKBr-3 cells was respectively 2- and 25-fold lower than that of anti-gp125 CILs and unmodified liposomes. Furthermore, anti-gp185 CILs significantly inhibited neither the phytohaemagglutin response of normal lymphocytes nor protein synthesis of gp185-negative T24 bladder cancer. Quantitative analysis of cell-associated doxorubicin revealed that, compared with anti-gp125 CILs, anti-gp185 CILs required, respectively 4.5 and 4.3 times less doxorubicin association in SKBR-3 and MKN-7 cells, for 50% cytotoxicity. In addition, flow cytometric analysis showed that both SKBr-3 and MKN-7 internalised more anti-gp185 CILs and processed them more efficiently than anti-gp125 CILs. These results suggest that anti-gp185 CILs act selectively against gp185-expressing cancer cells and that gp185 is a more sensitive antigen for CIL cytotoxicity associated with endocytosis activity.
Suzuki
S
S
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Uno
S
S
Fukuda
Y
Y
Aoki
Y
Y
Masuko
T
T
Hashimoto
Y
Y
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004337:Drug Carriers; D004705:Endocytosis; D005434:Flow Cytometry; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000911:Antibodies, Monoclonal; D004317:Doxorubicin; D004337:Drug Carriers; D000922:Immunotoxins; D008081:Liposomes; D018719:Erb-b2 Receptor Tyrosine Kinases