Gw. Krystal et al., INDUCTION OF APOPTOSIS AND INHIBITION OF SMALL-CELL LUNG-CANCER GROWTH BY THE QUINOXALINE TYRPHOSTINS, Cancer research, 57(11), 1997, pp. 2203-2208
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.