MATRIX METALLOPROTEINASE INHIBITOR BB-94 (BATIMASTAT) INHIBITS HUMAN COLON-TUMOR GROWTH AND SPREAD IN A PATIENT-LIKE ORTHOTOPIC MODEL IN NUDE-MICE

Matrix metalloproteinases have been implicated in the growth and sprea d of metastatic tumors. This role was investigated in an orthotopic tr ansplant model of human colon cancer in nude mice using the matrix met alloproteinase inhibitor BB-94 (batimastat). Fragments of human colon carcinoma (1-1.5 mm were surgically implanted orthotopically on the co lon in 40 athymic nu/nu mice. Administration of BB-94 or vehicle (phos phate buffered saline, pH 7.4, containing 0.01% Tween 80) commenced 7 days after tumor implantation (20 animals/group). Animals received 30 mg/kg BB-94 i.p. once daily for the first 60 days and then 3 times wee kly. Treatment with BB-94 caused a reduction in the median weight of t he primary tumor from 293 mg in the control group to 144 mg in the BB- 94 treated group (P < 0.001). BB-94 treatment also reduced the inciden ce of local and regional invasion, from 12 of 18 mice in the control g roup (67%) to 7 of 20 mice in the treated group (35%). Six mice in the control group were also found to have metastases in the liver, lung, peritoneum, abdominal wall, or local lymph nodes. Only two mice in the BB-94 group had evidence of metastatic disease, in both cases confine d to the abdominal wall. The reduction in tumor progression observed i n the BB-94-treated group translated into an improvement in the surviv al of this group, from a median survival time of 110 days in the contr ol group to a median survival time of 140 days in the treated group (P < 0.01). Treatment with BB-94 was not associated with any obvious tox ic effect, and these results suggest that such agents may be effective as adjunctive cancer therapies.