Antitumor activity of T-2 toxin-conjugated monoclonal antibody to murine thymoma.
T-2 toxin (T-2(4)), one of the trichothecene mycotoxins produced by various gerera of Fusarium spp., is a potent inhibitor to the syntheses of protein and DNA in mammalian cells. The selective cytotoxicity of T-2 toxin-conjugated anti-EL-4 monoclonal antibodies (T-2-mAb) was investigated against murine thymoma EL-4 cells in vitro and in vivo systems. At first T-2 was converted to T-2 hemiglutarate by glutaric anhydride. Then T-2 hemiglutarate was activated to 3-[4-(N-succinimidoxycarbonyl)-butyryl]-T-2 (T-2-G-OSu) by N-hydroxysuccinimide. Thus obtained T-2-G-OSu was conjugated with mAb specific for EL-4 cells. The T-2-mAb markedly inhibited the proliferation of cultured EL-4 cells, but no such cytotoxic effect was observed against irrelevant SP2/0 cells. The cytotoxicity of T-2-conjugated normal gamma globulin (T-2-nGG) against EL-4 cells was far less than that of the above T-2-mAb. Ammonium chloride and monensin, inhibitors of lysosomal enzymes, enhanced the cytotoxicity of T-2-mAb. The presence of both 2-deoxyglucose together with sodium azide, inhibitors of energy-dependent reaction, reduced the cytotoxicity of T-2-mAb. Therefore, the selective binding to the target cells followed by an energy-dependent endocytosis and an intracellular liberation of T-2 by hydrolysis may account for the cytotoxicity of the T-2-mAb. In mice pre-transplanted with EL-4 cells, T-2-mAb increased the mean survival time (MST) with a direct dosage dependence.(ABSTRACT TRUNCATED AT 250 WORDS)
Ohtani
K
K
Department of Toxicology and Microbial Chemistry, Faculty of Pharmaceutical Sciences, Science University of Tokyo, Japan.
Murakami
H
H
Shibuya
O
O
Kawamura
O
O
Ohi
K
K
Chiba
J
J
Otokawa
M
M
Ueno
Y
Y
D000818:Animals; D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D000970:Antineoplastic Agents; D001386:Azides / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D000922:Immunotoxins / Q000494:pharmacology*; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D012717:Sesquiterpenes / Q000494:pharmacology*; D019810:Sodium Azide; D013605:T-2 Toxin / Q000494:pharmacology*; D013945:Thymoma / Q000188:drug therapy* / Q000276:immunology; D013953:Thymus Neoplasms / Q000188:drug therapy* / Q000276:immunology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D001386:Azides; D000922:Immunotoxins; D012717:Sesquiterpenes; D019810:Sodium Azide; D003847:Deoxyglucose; D013605:T-2 Toxin