Batimastat (BB-94)

Batimastat (BB-94) inhibits matrix metalloproteinases of equine laminitis

Equine Vet J Suppl 1998 Sep;(26):119-24.9932102 10.1111/j.2042-3306.1998.tb05130.x

A method for culturing explants of lamellar hoof was developed to investigate the process of lamellar separation that occurs in laminitis. Explants, consisting of hoof wall, dermal and epidermal lamellae and the adjacent sub-lamellar connective tissue remained intact when cultured in tissue culture medium for 2 days. However, when cultured in the presence of the matrix metalloproteinase (MMP) activator aminophenylmercuric acetate (APMA), the lamellae separated when tension was applied by pulling the hoof wall in an opposite direction to the connective tissue. The separation occurred between the epidermal basal cells and the basement membrane therefore mimicking the lesion of laminitis. Electrophoresis of culture medium from control hoof explants into gradient polyacrylamide gels co-polymerised with gelatin revealed that the explants had produced 2 gelatinases of molecular weight 92 and 72 kDa corresponding to EqMMP-9 and EqMMP-2 respectively. Minor bands of lower molecular weight were the active forms of these enzymes. The zymograms of culture medium from APMA treated explants revealed an increase in the amount of active MMPs. Equine polymorphs cultured for 2 days produced only EqMMP-9. Lamellar explant medium from horses with acute laminitis contained increased amounts of zymogen and active EqMMP-2 and EqMMP-9 particularly in explants from the fore hooves. Zymography of homogenates of normal lamellar hoof tissue revealed only EqMMP-2 and a minor active band. However, homogenates of lamellar tissue from horses with laminitis showed that EqMMP-9 was present as well as increased EqMMP-2 in both zymogen and active forms. Addition of the MMP inhibitor Batimastat (BB-94) to the culture medium of APMA treated explants prevented lamellar separation. BB-94 incubated with polyacrylamide strips containing the MMPs from laminitis affected lamellar explants inhibited enzymatic activity at a concentration of 1 mmol/l. It is concluded that activation of MMPs may be responsible for the lamellar separation seen in laminitis and that MMP inhibitors may be useful clinically for preventing this process.

Batimastat. BB 94, collagenase inhibitors-1

Drugs R D 1999 Feb;1(2):139-41.10566008 10.2165/00126839-199901020-00005

Influence of the matrix metalloproteinase inhibitor Batimastat (BB-94) on periodontal bone destruction in Sprague-Dawley rats

J Periodontal Res 2004 Aug;39(4):269-74.15206921 10.1111/j.1600-0765.2004.00740.x

Background: Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading most macromolecules of the extracellular matrix. It has been assumed that an association exists between MMP activity and periodontal disease progression, but the precise role of MMPs in disease progression is still not fully clarified. Batimastat, or BB-94, is a synthetic broad-spectrum MMP inhibitor not previously examined in periodontal research. If there is an association between MMP activity and periodontal disease progression, then batimastat might be expected to reduce the progression of experimental periodontal disease in rats. Objectives: The objective of the present study was to determine the effects of batimastat on periodontal status in healthy Sprague-Dawley (SPRD) rats as well as in rats with ligature-induced experimental periodontal disease. Methods and results: Periodontal bone destruction was used as a means of evaluating periodontal destruction by measuring periodontal bone loss on defleshed rat jaws and periodontal bone support on radiographs of the jaws. There was significantly more periodontal bone destruction in the groups treated with batimastat than in the placebo and control groups. This accounted for both ligated and non-ligated groups, irrespective of whether periodontal bone loss (p < 0.05) or periodontal bone support (p < 0.05) were measured. Conclusion: In conclusion, the results of this study did not support the hypothesis that the MMP inhibitor batimastat could reduce the progression of experimental periodontal disease in rats. Instead, significantly increased bone destruction was found in rats treated with batimastat.

Phase I study of intrapleural Batimastat (BB-94), a matrix metalloproteinase inhibitor, in the treatment of malignant pleural effusions

Clin Cancer Res 1999 Mar;5(3):513-20.10100701

Tumor cells and associated stromal cells secrete matrix metalloproteinases (MMPs), contributing to invasion, angiogenesis, and metastasis. Batimastat (BB-94) is a broad-spectrum MMP inhibitor that causes resolution of ascites and/or tumor growth delay in animal models of breast, ovarian, and colorectal cancer. We recruited 18 patients with cytologically positive malignant pleural effusions into a Phase I study of intrapleural BB-94. Three patients received single doses of BB-94 at each dose level: 15, 30, 60, 105, 135, and 300 mg/m2. Two patients were retreated with a second course at 60 and 105 mg/m2. BB-94 was detectable in plasma 1 h after intrapleural administration, and peak levels of 20-200 ng/ml occurred after 4 h to 1 week. BB-94 persisted in the plasma for up to 12 weeks, at levels exceeding the IC50s for target MMPs. Peak values were higher, and persistence in the plasma was longer after higher doses of BB-94. The treatment was well tolerated. Toxic effects included low-grade fever for 24-48 h (6 of 18 patients, 33%) and reversible asymptomatic elevation of liver enzymes (8 patients, 44%). Toxicity seemed unrelated to BB-94 dose or plasma levels. Sixteen patients evaluable for response required significantly fewer pleural aspirations in the 3 months after BB-94 compared with the 3 months before. Seven patients (44%) required no further pleural aspiration until death/last follow-up. After 1 month, patients treated with 60-300 mg/m2 BB-94 had significantly better dyspnea scores, indicating improved exercise tolerance, compared with baseline scores the day after BB-94. The maximum tolerated intrapleural dose remains to be defined, but it is clear that intrapleural BB-94 is well tolerated, with evidence of local activity.

Matrix metalloproteinase inhibitor BB-94 (Batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice

Cancer Res 1994 Sep 1;54(17):4726-8.8062271

Matrix metalloproteinases have been implicated in the growth and spread of metastatic tumors. This role was investigated in an orthotopic transplant model of human colon cancer in nude mice using the matrix metalloproteinase inhibitor BB-94 (Batimastat). Fragments of human colon carcinoma (1-1.5 mm) were surgically implanted orthotopically on the colon in 40 athymic nu/nu mice. Administration of BB-94 or vehicle (phosphate 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 weekly. Treatment with BB-94 caused a reduction in the median weight of the 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 incidence of local and regional invasion, from 12 of 18 mice in the control group (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 confined to the abdominal wall. The reduction in tumor progression observed in the BB-94-treated group translated into an improvement in the survival of this group, from a median survival time of 110 days in the control 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 toxic effect, and these results suggest that such agents may be effective as adjunctive cancer therapies.