Reversal of adriamycin resistance with chimeric anti-ganglioside GM2 antibody.
Ganglioside GM2 is one of the major cell-surface gangliosides expressed in human tumors. We earlier established a mouse/human IgG1 chimeric anti-GM2 antibody, KM966, which displayed anti-tumor activity in human tumor cells both in vitro and in vivo. In this study, we have screened for changes in ganglioside expressions in several drug-resistant human cancer cell lines to examine the modulation of drug resistance by immunotherapy with anti-ganglioside antibodies. Increased GM2 expression, detected by flow cytometry and thin-layer chromatography, was observed in the SBC-3/ADM and AdrR MCF7 adriamycin-resistant cell lines, in contrast with their parental lines. In other related gangliosides, ganglioside GD2 levels in AdrR MCF7 were higher than those in MCF7 cells. We confirmed increased N-acetylgalactosaminyltransferase mRNA in adriamycin-resistant cell lines, as compared with the parental cells, by Northern-blot analysis. Moreover, to investigate the possibility of exploiting the anti-tumor activity of KM966 in order to overcome resistance to adriamycin, we investigated the antibody-dependent cell-mediated cytotoxity of human peripheral mononuclear blood cells and the complement-dependent cytotoxity of human serum with KM966 against SBC-3, SBC-3/ADM, MCF7 and AdrR MCF7. Significantly higher killing via KM966 was observed in SBC-3/ADM and AdrR MCF7 cells as compared with the parental cells. This suggests that passive immunotherapy using KM966 against human adriamycin-resistant cancer may be useful for overcoming resistance to adriamycin.
Fukumoto
H
H
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Nishio
K
K
Ohta
S
S
Hanai
N
N
Saijo
N
N
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D003165:Complement System Proteins / Q000276:immunology; D004317:Doxorubicin; D004351:Drug Resistance; D005678:G(M2) Ganglioside / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D007963:Leukocytes, Mononuclear / Q000276:immunology; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D005678:G(M2) Ganglioside; D004317:Doxorubicin; D003165:Complement System Proteins; D017350:N-Acetylgalactosaminyltransferases