Novel doxorubicin-monoclonal anti-carcinoembryonic antigen antibody immunoconjugate activity in vitro.
Doxorubicin was modified with five different heterobifunctional reagents to produce drug analogs containing 3'-N-amide or C-13 hydrazone linkage with maleimide. Synthesis and characterization of two new reagents, 4-maleimidobenzohydrazide trifluoroacetate salt (13) and N-(4-maleimidobenzoyl)-6-aminocaprohydrazide trifluoroacetate salt (14) are described here. All Dox maleimido derivatives were conjugated to thiolated anti-carcinoembryonic antigen monoclonal antibody, 11-285-14, via a Michael addition reaction. Antibody-directed cytotoxicity was demonstrated with the MTT assay using combinations of antigen-positive and antigen-negative cell lines. The immunoconjugates prepared from Dox 3'-N-amide analogs are not active in vitro, however, Dox(hydrazone-linked) immunoconjugates are selectively toxic to the CEA positive cell line.
Lau
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School of Pharmacy, Memorial University of Newfoundland, St. John's, Canada.
Bérubé
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Ford
C H
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Gallant
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D000230:Adenocarcinoma / Q000188:drug therapy; D000903:Antibiotics, Antineoplastic / Q000276:immunology / Q000633:toxicity*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000633:toxicity*; D002272:Carcinoembryonic Antigen / Q000276:immunology / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D004317:Doxorubicin / Q000276:immunology / Q000633:toxicity*; D006801:Humans; D000922:Immunotoxins / Q000276:immunology / Q000633:toxicity*; D013439:Sulfhydryl Reagents / Q000737:chemistry; D013778:Tetrazolium Salts; D013844:Thiazoles; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D000922:Immunotoxins; D013439:Sulfhydryl Reagents; D013778:Tetrazolium Salts; D013844:Thiazoles; D004317:Doxorubicin; C022616:thiazolyl blue