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Antitumor activity of T-2 toxin-conjugated monoclonal antibody to murine thymoma
K Ohtani1, H Murakami, O Shibuya
1Department of Toxicology and Microbial Chemistry, Faculty of Pharmaceutical Sciences, Science University of Tokyo, Japan.
Abstract:
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)
Insights
T-2 toxin-conjugated monoclonal antibodies (T-2-mAb) show selective toxicity against EL-4 cancer cells. This targeted approach inhibits cancer cell proliferation and improves survival rates in mice.
Area of Science:
- Immunology
- Toxicology
- Biochemistry
Background:
- T-2 toxin is a potent mycotoxin inhibiting protein and DNA synthesis.
- Targeted delivery of cytotoxic agents offers a promising strategy for cancer therapy.
Purpose of the Study:
- To investigate the selective cytotoxicity of T-2 toxin-conjugated anti-EL-4 monoclonal antibodies (T-2-mAb).
- To evaluate the efficacy of T-2-mAb against murine thymoma EL-4 cells in vitro and in vivo.
Main Methods:
- T-2 toxin was chemically modified to create T-2-G-OSu.
- T-2-G-OSu was conjugated to monoclonal antibodies (mAbs) specific for EL-4 cells.
- Cytotoxicity was assessed in cultured EL-4 cells and in a murine cancer model.
Main Results:
- T-2-mAb demonstrated significant inhibition of EL-4 cell proliferation, with minimal effect on irrelevant cells.
- Lysosomal enzyme inhibitors enhanced T-2-mAb cytotoxicity, while energy depletion reduced it.
- T-2-mAb treatment increased the mean survival time in mice bearing EL-4 tumors.
Conclusions:
- The cytotoxicity of T-2-mAb relies on selective binding, energy-dependent endocytosis, and intracellular T-2 release.
- T-2-mAb represents a potential targeted therapy for EL-4-mediated cancers.