Escape mechanisms of human leukemic cells to long-term immunotoxin treatment in an in vitro experimental model.
In kinetic assays, an anti-CD5-ricin A chain (ST.I-RTA) immunoconjugate (immunotoxins, IT) specifically inhibited up to 40% the protein synthesis of Jurkat target cells within the first 40 hr. Longer exposures of leukemia cells to ST.I-RTA resulted in a progressively higher number of target cells escaping IT treatment and becoming resistant to further treatment with ST.I-RTA even in the presence of the RTA-IT enhancer monensin. Resistant Jurkat cells proliferated at the same rate as control untreated cells, and were as sensitive as control cells to a transferrin-RTA IT, indicating that the ST.I-RTA-resistant tumor-cell population did not become insensitive to the enzymatic activity of RTA. Binding studies revealed that the anti-CD5 IT treatment induced a transient modulation of CD5 antigens but not of the functionally related CD3 antigens. The CD5 antigens were re-expressed at the cell surface following removal of the IT molecules from the culture medium with 1.1% of the total CD5 Ag being re-expressed per hr. When our experimental data on the kinetics of cell intoxication by the IT were corrected for the proliferative potential of the resistant and of the sensitive tumor-cell populations, it appeared that the effect of ST.I-RTA treatment on Jurkat cells was only to delay cell growth for a limited time period (20 hr) without reducing effectively the tumor-cell burden. Our results may have implications for the long-term treatment of target tumor cells with IT.
Chignola
R
R
Istituto di Immunologia e Malattie Infettive, Università di Verona, Italy.
Pasti
M
M
Candiani
C
C
Franceschi
A
A
Anselmi
C
C
Tridente
G
G
Colombatti
M
M
D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology*; D018956:CD5 Antigens; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004351:Drug Resistance / Q000502:physiology; D005069:Evaluation Studies as Topic; D006801:Humans; D000922:Immunotoxins / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007945:Leukemia, Lymphoid / Q000188:drug therapy* / Q000378:metabolism*; D012276:Ricin / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018956:CD5 Antigens; D000922:Immunotoxins; D012276:Ricin