Synthetic inhibitor of matrix metalloproteinases (batimastat) reduces prostate cancer growth in an orthotopic rat model

BACKGROUND. Increased concentrations of metalloproteinases are associated w ith the invasive and metastatic behavior of several human malignant tumors. Normally, enzymatic activity is tightly regulated by nonspecific mechanism s and specific inhibitors. The aim of the study was to determine the potent ial of a synthetic metalloproteinase inhibitor, batimastat, to show its in vitro effect on MatLyLu cancer cells and its in vivo effect on tumor growth in orthotopic cancer (R3327 Dunning tumor) in rats. METHODS. In vitro, a dose response curve of batimastat was generated over 4 days using the MTT assay. Prostate cancer was injected in vivo in male Cop enhagen rats by inoculating R3327 Dunning tumor cells (MatLyLu) into the ve ntral prostatic lobe of 30 rats. Each of 10 rats received batimastat (30 mg /kg body weight) or vehicle administered once a day by i.p. application beg inning the day of cell inoculation. Ten rats remained untreated. The effect on local tumor growth was evaluated by measuring tumor weights 20 days aft er tumor cell inoculation. RESULTS. Significant inhibition of tumor cell proliferation in vitro occurr ed at 400 and 4,000 ng/ml batimastat. After orthotopic cell inoculation, tu mors grew to mean weights of 18.9 g in the control group without treatment, to 22.3 g in the vehicle group, and to 11.1 g in the treated group. Ln com parison to the control group and to the vehicle group, tumor weights increa sed significantly less under treatment with batimastat. CONCLUSIONS. Batimastat is able to reduce tumor growth in the standard pros tate cancer model. Using this model, activity against cancer progression of future inhibitory agents can be reliably assessed. (C) 2000 Wiley-Liss, In c.