Three synthetic irreversible
enzyme inhibitors (75 microM di-iso-propylphosphorofluoridate (
DFP), 310 microM N alpha-p-tosyl-
L-lysine (
TLCK) and 240 microM L-1-tosylamide-2-phenylethyl (
TPCK) chloromethyl
ketone), as well as the transition state analogue
chymostatin, inhibit the development of Lewis
lung adenocarcinoma (3LL) in C57
BI/6 mice, when 3LL cells are treated once and for a limited period (60 min) prior to grafting. These compounds demonstrate divergent
protease specificity and, in the case of
TLCK and
TPCK, convergent reactivity toward the highly conserved
protein kinase catalytic subunit. Using 200 microM
chymostatin and low doses (25-40 microM) of the irreversible
enzyme inhibitors, the antimetastatogenic effect is revealed to be specific, as primary
tumor development is not affected. Although no direct experimental evidence can be forwarded, our results fit with the concept that the motile metastatogenic 3LL cells may constitute a phenotype which, in contrast to the resident cells from the primaries, responds to these
enzyme inhibitors in a highly sensitive manner.