INDUCTION OF APOPTOSIS AND INHIBITION OF SMALL-CELL LUNG-CANCER GROWTH BY THE QUINOXALINE TYRPHOSTINS

Coexpression of the Kit receptor tyrosine kinase and its ligand, stem cell factor (SCF), occurs in a high proportion of small cell lung canc ers (SCLCs) and drives an autocrine loop that enhances proliferation, To determine whether this autocrine loop affects apoptosis, SCLC cells expressing only SCF or both SCF and Kit were deprived of growth facto rs for 72 h and the relative number of cells undergoing apoptosis was assessed using nuclear DNA content and terminal deoxynucleotidyl trans ferase-mediated dUTP nick end labelling assays, Coexpression of SCF an d Kit inhibited apoptosis; apoptosis could, in turn, be enhanced by th e addition of the quinoxaline tyrosine kinase inhibitors, which are sp ecific antagonists of the platelet-derived growth factor receptor and Kit. Treatment of the H526 cell line, which is growth-stimulated by so luble SCF, with AG1296 resulted in a marked decrease in growth and an increase in apoptosis in a dose-dependent fashion, Growth inhibition c orrelated well with the inhibition of Kit tyrosine phosphorylation, Th e AG1296 compound at its maximum soluble concentration inhibited the g rowth of 5 of 6 SCLC cell lines in complete medium by an average of 50 %, These data suggest that optimized pharmacological inhibitors of Kit activity may be a new class of compounds potentially useful in the tr eatment of SCLC.