CONTROL OF LYMPHATIC AND HEMATOGENOUS METASTASIS OF A RAT MAMMARY-CARCINOMA BY THE MATRIX METALLOPROTEINASE INHIBITOR BATIMASTAT (BB-94)

We examined the effects of the synthetic matrix metalloproteinase inhi bitor batimastat (BE-94) on lung colonization and spontaneous metastas is of a rat mammary carcinoma, HOSP.1P. This tumor expresses both late nt and active forms of the matrix metalloproteinases MMP-2 and MMP-9, although the former, as in human breast cancer, is the most prominent, Administration of batimastat (6 x 30 mg/kg i.p.) inhibited by up to 8 0% both the number and median weights of HOSP.1P lung colonies followi ng i.v. inoculation of cells. This implies an effect both on seeding e fficiency and subsequent tumor development. In spontaneous metastasis assays, limited treatment with batimastat (commencing when s.c. tumors were established and continuing until 5 or 14 days after their surgic al removal) significantly inhibited lung metastasis but had little eff ect on lymphatic metastasis. However, when treatment was initiated 2 d ays prior to surgery and continued until day 70, 100% of animals survi ved to day 120 when there was no evidence of metastatic disease. All c ontrol animals (n = 25) in two separate experiments died before day 10 0 with lymphatic, lung, and extrapulmonary metastases. Taken together, these data suggest that lymphatic dissemination by HOSP.1P tumor cell s is less susceptible to inhibition by batimastat than vascular invasi on, but that long-term treatment can effectively prevent the outgrowth of putative micrometastases in both lymph nodes and lungs, allowing s ustained tumor-free survival.