Selective cytotoxicity against tumor cells by cisplatin complexed to antitumor antibodies via carboxymethyl dextran.
Cis-diamminedichloroplatinum (II) (cis-DDP) and its structural analogue cis-diamminediaquoplatinum(II) nitrate (cis-aq) were complexed via an intermediate dextran carrier to antibodies specifically reactive with B lymphoma cells (38C-13). The potential use of these drugs in site-directed immunotargeting was evaluated. The two platinum(II) compounds were previously shown to form pharmacologically active complexes with carboxymethyl dextran (CM-dex). For the purpose of preparing drug-antibody complexes, CM-dex was first conjugated to idiotypic antibodies that recognize a specific membrane IgM on the B lymphoma cells. The conjugates were prepared by a modified water-soluble carbodiimide method in which N-hydroxysuccinimide was used to enhance the coupling reaction. The conjugation was followed by separation of the CM-dex-IgG conjugates from unconjugated CM-dex or IgG. The platinum(II) compounds were then complexed to the CM-dex-IgG resulting in complexes carrying up to 50 mole drug/mole IgG. Both cis-DDP and cis-aq complexes of CM-dex-antibody conjugates maintained most of the original cell-binding activity of the antibodies. An in vitro assay was used to demonstrate selective binding to tumor cells in which the target cells were treated with specific immune complexes and washed before culture. In this assay the specific complexes showed preferential cytotoxicity for the B lymphoma cells in comparison to the free drugs, drug CM-dex, or nonspecific immune complexes.
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage; D000912:Antibodies, Neoplasm / Q000008:administration & dosage; D001402:B-Lymphocytes / Q000276:immunology; D002945:Cisplatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects; D003911:Dextrans; D007074:Immunoglobulin G / Q000008:administration & dosage; D007130:Immunoglobulin Idiotypes / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D008223:Lymphoma / Q000276:immunology; D051379:Mice; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism*
D000888:Antibodies, Anti-Idiotypic; D000912:Antibodies, Neoplasm; D003911:Dextrans; D007074:Immunoglobulin G; D007130:Immunoglobulin Idiotypes; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; C034297:diamminediaqua platinum(II); C014392:carboxymethyl dextran; D002945:Cisplatin