Cyclosporin A and cyclosporin SDZ PSC 833 enhance anti-CD5 ricin A-chain immunotoxins in human leukemic T cells.
Recent studies have shown that cyclosporin A (CsA) may affect ricin A-chain immunotoxin (RTA-IT) therapy. In this study, we evaluated the ability of CsA and its nonimmunosuppressive analog, SDZ PSC 833, to enhance anti-CD5 T101 RTA-ITs in vitro. Both 4 mumol/L CsA and 4 mumol/L SDZ PSC 833 significantly and specifically enhanced the cytotoxic activity of T101 RTA-IT on the human lymphoblastic T-cell line, CEM III (101-fold and 105-fold, respectively). Furthermore, these Cs also enhanced the cytotoxicity of the more potent T101 F(ab')2 RTA-IT (ninefold and eightfold, respectively). The effect of human plasma, originating from four patients enrolled in a phase I high-dose CsA regimen, was examined on T101 RTA-IT cytotoxicity on CEM III cells. In each case, with plasma CsA levels between 3,090 and 4,860 ng/mL (2.5 to 4 mumol/L), a significant increase in T101 RTA-IT-mediated cytotoxicity was observed ranging from 31% to 60%. Neither CsA nor SDZ PSC 833 affected the rate of RTA-IT binding, internalization, intracellular trafficking, or degradation. Analysis of internalized T101 RTA-IT molecules showed that these were essentially intact, which suggests that these enhancers may act only on a small population of RTA-ITs that escapes present investigational techniques. In conclusion, because the concentrations used are clinically achievable, Cs appear to be promising agents for in vivo enhancement of RTA-ITs.
Jaffrézou
J P
JP
Laboratoire de Pharmacologie et de Toxicologie Fondamentales, Centre National de la Recherche Scientifique, Toulouse, France.
Sikic
B I
BI
Laurent
G
G
D015703:Antigens, CD / Q000276:immunology*; D018956:CD5 Antigens; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D000922:Immunotoxins / Q000378:metabolism / Q000494:pharmacology*; D007938:Leukemia / Q000097:blood; D014176:Protein Biosynthesis; D012276:Ricin / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects
D015703:Antigens, CD; D018956:CD5 Antigens; D003524:Cyclosporins; D000922:Immunotoxins; D016572:Cyclosporine; D012276:Ricin; C070272:valspodar