EFFECT OF MATRIX METALLOPROTEINASE INHIBITORS ON TUMOR-GROWTH AND SPONTANEOUS METASTASIS

Four potent, synthetic inhibitors of matrix metalloproteinases (MMPs) were assessed as inhibitors of tumor growth and spontaneous metastasis to the lung, Mat Ly Lu rat prostate tumor, LOX human melanoma and M27 murine Lewis lung tumor were implanted subcutaneously (s.c.) in mice and allowed to grow for 3-12 days, The lungs of the tumor-bearing mice were then removed and implanted s.c. into untreated mice, and the out growth of secondary tumors from the implanted lungs measured, The inci dence and rate of outgrowth of secondary tumors increased with the len gth of primary turner growth, validating these measurements as indices of spontaneous metastasis to the lung, Compounds were tested by s.c. implantation of minipumps which delivered compound throughout the peri od of primary tumor growth and spontaneous metastasis to the lung at s teady-state drug concentrations orders of magnitude greater than the c oncentrations needed to either inhibit collagenase, gelatinase or stro melysin in vitro, Inhibitor treatment slowed the growth of primary s.c . Mat Ly Lu and LOX tumors by 40-60% but had no significant effect on the growth of primary M27 tumors, Surprisingly, inhibitor treatment ha d no significant effect on the ability of the lung to generate seconda ry tumors when reimplanted s.c. in untreated mice, Because of the poss ible importance of cathepsins B, H and L in tumor growth and metastasi s, the irreversible inhibitor E-64 was also infused by s.c. minipump, E-64 had no effect on the growth or spontanous metastasis of Mat Ly Lu or M27 tumors.