Inhibition of experimental blood-borne lung metastasis by protease inhibitors.

The inhibitory effects of protease inhibitors on blood-borne metastasis in male Donryu rat lung were studied. Injection i.v. of 10(6) Yoshida ascites hepatoma AH7974 cells induced about 118 +/- 92 (S.D.) metastatic foci in rat lung after 3 weeks. Leupeptin (50 mg/kg body weight twice a day), injected i.p. from 2 days before to 4 days after the inoculation of tumor cells, reduced the number of metastatic foci to about 49 +/- 45 (p less than 0.005). Leupeptin also suppressed the formation of metastatic foci of Yoshida ascites hepatoma AH100B cells (p less than 0.001). Elastatinal (100 mg/kg body weight twice a day) and chymostatin (100 mg/kg body weight once a day) did not inhibit formation of metastatic foci of AH7974 cells. Injection i.v. of 10(6) AH7974 cells induced pulmonary thrombi within 1 hr. Leupeptin (50 mg/kg body weight twice a day) reduced the number of thrombi from 1298 +/- 395 to 646 +/- 218, when injected i.p. for 2 days before the inoculation of the cells (p less than 0.005). Chymostatin and elastatinal did not significantly change the number of pulmonary thrombi. These results indicate that leupeptin inhibited metastasis formation and suggest that this effect may be due to the inhibition of thrombus formation after the arrest of circulating tumor cells.