Three synthetic irreversible enzyme inhibitors (75 µm di-isopropylphosphorofluoridate (DFP), 310 µm Nα-p-tosyl-L-lysine (TLCK) and 240 µm 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 Bl/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 µm chymostatin and low doses (25–40 µm) 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.
Dedicated to Joszeph Jaffé. This work would not be, had he not been.