Cyclosporin A and cyclosporin SDZ PSC 833 enhance anti-CD5 ricin A- chain
immunotoxins in human leukemic T cells
JP Jaffrezou, BI Sikic and G Laurent
Laboratoire de Pharmacologie et de Toxicologie Fondamentales, Centre
National de la Recherche Scientifique, Toulouse, France.
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.
Volume 83,
Issue 2,
pp. 482-489,
01/15/1994
Copyright © 1994 by The American Society of Hematology
