Antibodies to an autostimulatory growth factor (IL-2) or its receptor induce death of leukemogenic cells.
We show for the first time that Ab-mediated antagonism of growth factor activity can induce death of all cells in clonal populations surviving and growing by an autostimulatory mechanism. Models of autostimulatory leukemia were generated by transfecting a mouse IL-2-dependent cell line (FD.C/2) with vectors directing production of IL-2 by these cells. One series of clones grew in a density-dependent manner in the absence of exogenous IL-2 and produced tumors in syngeneic mice. Although these clones released relatively small amounts of IL-2, their growth and survival was only partially inhibited by Abs to IL-2 or the IL-2R. Another autostimulatory clone was derived, using a different vector, which produced significantly less IL-2. Treatment of cells of this clone with Abs to IL-2 or its receptor resulted in death of all cells. These data demonstrate that Abs that antagonize growth factor action can induce the death of cells transformed by autostimulatory mechanisms. They suggest that while autostimulatory tumors are relatively resistant to Abs that block growth factor action, this is a quantitative phenomenon, and competitive antagonists of growth factor action of sufficiently high affinity may provide effective and specific adjuvants to the treatment of such tumors.
Orban
P C
PC
The Biomedical Research Centre, The University of British Columbia, Vancouver, Canada.
Schrader
J W
JW
D000818:Animals; D001323:Autoantibodies / Q000494:pharmacology*; D001667:Binding, Competitive / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002999:Clone Cells; D005822:Genetic Vectors / Q000276:immunology; D006131:Growth Inhibitors / Q000276:immunology / Q000494:pharmacology*; D007113:Immunity, Innate; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology*; D007942:Leukemia, Experimental / Q000209:etiology / Q000276:immunology* / Q000473:pathology*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D012190:Retroviridae / Q000235:genetics; D014407:Tumor Cells, Cultured
D001323:Autoantibodies; D006131:Growth Inhibitors; D007376:Interleukin-2; D015375:Receptors, Interleukin-2