batimastat and Body-Weight

Bleomycin-induced pulmonary fibrosis is known to be associated with the increased activity of two gelatinases, matrix metalloproteinase (MMP)-2 and MMP-9, in bronchoalveolar lavage (BAL). This study has investigated the effect of a synthetic inhibitor of MMP, batimastat, on the development of pulmonary fibrosis induced by bleomycin administration in mice. Animals were intranasally instilled with saline or bleomycin (0.5 mg in 100 microl per mouse). Batimastat (30 mg/kg) or vehicle alone was administered by intraperitoneal injection 24 h and 1 h before saline or bleomycin instillation, and then daily at the same dosage until the end of the study. Fifteen days after bleomycin administration, BAL was performed and the lung was removed. Treatment of mice with batimastat significantly reduced bleomycin-induced lung fibrosis, as shown in the lung by histopathological examination and by a decrease in hydroxyproline levels. Batimastat also prevented the increase in BAL macrophage and lymphocyte numbers, whereas it did not show any effect on the increased expression of active transforming growth factor-beta (TGF-beta) in BAL. Batimastat treatment was effective in reducing MMP-2 and MMP-9 activity as well as the tissue inhibitor of metalloproteinase-1 (TIMP-1) level in BAL. These results suggest that administration of the MMP inhibitor batimastat is useful in preventing experimental pulmonary fibrosis induced by bleomycin and raises the possibility of a therapeutic approach to human pulmonary fibrotic disease.

Topics: Animals; Bleomycin; Body Weight; Bronchoalveolar Lavage Fluid; Cell Count; Hydroxyproline; Male; Matrix Metalloproteinase Inhibitors; Metalloendopeptidases; Mice; Mice, Inbred Strains; Phenylalanine; Protease Inhibitors; Pulmonary Fibrosis; Survival Rate; Thiophenes; Tissue Inhibitor of Metalloproteinases

Matrix metalloproteinases (MMPs) participate in basement membrane degradation, a critical step in invasion of cancer cells. We have previously shown that MMP inhibition of pancreatic cancers improves survival and decreases MMP production in vivo. The purpose of this study was to determine whether BB-94 was better than cytotoxic therapy and would increase the efficacy of cytotoxic therapy (gemcitabine) in a murine model of human pancreatic cancer. A human pancreatic adenocarcinoma cell line (HPAC) was injected into the pancreata of BALB/c nu/nu mice. The mice were randomized 7 days after cancer cell injection to receive vehicle control, BB-94, gemcitabine, or gemcitabine and BB-94 until death or sacrifice at 84 days. At necropsy, tumors were harvested, and the relative enzyme activities of MMP-2 and MMP-9 were determined by gelatin zymography. Active MMP-2 levels in serum were determined using an ELISA technique. Combination treatment with gemcitabine and BB-94 significantly reduced implantation rates and improved survival in mice with documented orthotopic tumors compared with either therapy alone or control. Tumor levels of active and latent MMP-2 were higher than those of MMP-9 in both treated and control mice. There was a significant reduction of tumor MMP-2 activity in mice treated with BB-94, gemcitabine, or gemcitabine and BB-94. Serum levels of active MMP-2 were reduced in all treated groups, with the greatest reduction occurring in mice treated with gemcitabine and BB-94. Combination therapy with gemcitabine and BB-94 reduces cancer implantation and improves survival compared to treatment with BB-94, gemcitabine, or vehicle control alone. MMP production was reduced in all treated groups, reflecting reduced tumor progression, which was particularly seen with combination therapy with gemcitabine and BB-94. This study supports combining MMP inhibition with cytotoxic therapy (gemcitabine) for patients with pancreatic cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Chromatography, Affinity; Deoxycytidine; Enzyme-Linked Immunosorbent Assay; Gemcitabine; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Pancreatic Neoplasms; Phenylalanine; Thiophenes; Time Factors; Tumor Cells, Cultured