ATG-saporin-S6 immunotoxin: a new potent and selective drug to eliminate activated lymphocytes and lymphoma cells.
Anti-thymocyte globulins (ATG) are currently used to prevent graft-versus-host disease in haematopoietic stem cell transplants from alternative donors and to treat and prevent acute organ rejection after transplantation. Many recent studies have demonstrated that ATG can also be beneficial in patients with myeloma, lymphoma, leukaemia and myelodysplastic syndrome. This study showed, for the first time, that the cytotoxic effect of ATG can been enhanced by conjugation with saporin-S6, which is one of the most stable and active type-1 ribosome-inactivating proteins. The ATG-saporin-S6 immunotoxin showed a strong cytotoxic effect on five lymphoma- and leukaemia-derived cell lines as well as on activated lymphocytes while sparing non-haematological cell lines. ATG-saporin-S6 induced a time-dependent activation of caspase-3/7 in RAJI cells. The caspase inhibitor Z-VAD-fmk partially rescued the cells that were treated with ATG-saporin-S6, suggesting that multiple cell death pathways, some of which are caspase independent, play a role in ATG-saporin-S6 toxicity. In our experiments ATG increased the complement-independent cytotoxicity of activated lymphocytes by a magnitude of 3-5 logs after conjugation. These findings suggest that the ATG-saporin-S6 immunotoxin is a promising therapeutic tool for many pathological conditions involving T lymphocytes and T and B neoplastic cells.
Polito
Letizia
L
Dipartimento di Patologia Sperimentale, Università di Bologna, Bologna, Italy.
Bortolotti
Massimo
M
Farini
Valentina
V
Pedrazzi
Manuela
M
Tazzari
Pier Luigi
PL
Bolognesi
Andrea
A
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000961:Antilymphocyte Serum / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D003165:Complement System Proteins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D054789:Ribosome Inactivating Proteins, Type 1 / Q000494:pharmacology*; D000076985:Saporins; D014407:Tumor Cells, Cultured
D000961:Antilymphocyte Serum; D000972:Antineoplastic Agents, Phytogenic; D000922:Immunotoxins; D009363:Neoplasm Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D000255:Adenosine Triphosphate; D003165:Complement System Proteins; D000076985:Saporins