Disease relevance of batimastat

• PURPOSE: We asked whether batimastat, given as adjuvant therapy after primary tumor resection, could inhibit local-regional tumor regrowth and the formation of lung metastases in a human breast cancer xenograft model [1].
• We also explored possible effects of batimastat on breast cancer cell viability and on the accumulation of specific messenger RNAs (mRNAs) [1].
• Inhibition of angiogenesis and murine hemangioma growth by batimastat, a synthetic inhibitor of matrix metalloproteinases [2].
• Four weeks later, PC3 human prostate cancer cells were injected directly into some of the implants, and daily treatment was begun with batimastat (a broad-spectrum MMP inhibitor) [3].
• METHODS: The effect of batimastat was studied in vivo on the formation of hemorrhaging, cavernous hemangiomas by eEnd.1 endothelioma cells injected subcutaneously in nude mice and on the angiogenic response induced by an endothelioma cell supernatant embedded in a pellet of reconstituted basement membrane (Matrigel) [2].

Psychiatry related information on batimastat

• Eighty-six athymic nude/nude mice underwent orthotopic implantation of 10(7) HPAC cells and were blindly randomized into four groups: (1) Control; (2) Batimastat, a matrix metalloproteinase inhibitor (MMPI) at 400 ng/ml qod; (3) EGFRI at 100 mg/kg qd; and (4) MMPI and EGRRI (both) [4].

High impact information on batimastat

• There were six mice (i.e., six implants) in each of four experimental arms: bone alone with and without batimastat and bone injected with PC3 cells with and without batimastat [3].
• Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice [1].
• The effect of batimastat treatment on the accumulation of mRNAs encoding specific MMPs and the tissue inhibitor of metalloproteinases-2 (TIMP-2) in cultured cells, primary tumors, and tumor regrowths was measured by RNA dot blotting and hybridization with complementary probes [1].
• Batimastat treatment did not affect cellular levels of MMP or TIMP-2 mRNAs [1].
• Batimastat significantly inhibited endothelial cell invasion in vitro through a layer of Matrigel, but it showed no direct cytotoxic activity [2].

Chemical compound and disease context of batimastat

• Ang II-induced mammalian target of rapamycin activation, [3H]leucine incorporation, and cellular hypertrophy were inhibited by pretreatment with either batimastat or CRM197 or by pretreatment with rapamycin or the EGFR tyrosine kinase inhibitor AG1478 [5].
• These results suggest a potentiation of the antineoplastic activity of cisplatin by batimastat and support the use of the two agents in combination in the treatment of ovarian cancer patients [6].
• 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 [7].
• Inhibition of MMP activity using the hydroxamate, zinc-chelating mimicers of collagen, Batimastat and Marimastat, has shown efficacy in reducing constrictive vascular remodeling 6 weeks after experimental angioplasty but not intimal hyperplasia [8].

Biological context of batimastat

• METHODS: Human MDA-MB-435 breast cancer cells were treated in vitro for 6 days with batimastat at concentrations ranging from 0.1 to 10.0 microM, and then viable cell counts were performed [1].
• PURPOSE: To study the role of matrix metalloproteinase in vascular tumors, we tested the antineoplastic activity of a synthetic inhibitor of matrix metalloproteinases, batimastat, on an experimental model of hemangioma, formed by murine endothelioma cells transformed by polyoma middle-T oncogene (eEnd.1) [2].
• We have examined the interaction of batimastat (BB-94) with a metalloproteinase [atrolysin C (Ht-d), EC 3.4.24.42] active site at 2.0-angstroms resolution (R = 16.8%) [9].
• The MMP inhibitor batimastat (BB-94) significantly reduced the BBB disruption and the increase in intracranial pressure irrespective of the time of batimastat administration (15 minutes before and 3 hours after meningococcal challenge) but failed to significantly reduce CSF white blood cell counts [10].
• Batimastat treatment also caused liver-specific overexpression of MMPs-2, -9, and mRNA up-regulation of angiogenesis factors and caspase-1, even in tumor-free animals [11].

Anatomical context of batimastat

• Batimastat at concentrations between 0.01 and 3.0 micrograms/ml had no direct cytotoxic effects on the in vitro growth of the cell lines [12].
• Taken together, these data suggest that lymphatic dissemination by HOSP.1P tumor cells is less susceptible to inhibition by batimastat than vascular invasion, but that long-term treatment can effectively prevent the outgrowth of putative micrometastases in both lymph nodes and lungs, allowing sustained tumor-free survival [13].
• We report that because of batimastat treatment, human breast carcinoma cells metastasized to the liver in nude mice and that an increase of liver metastases of murine T-cell lymphoma cells was observed in syngeneic mice [11].
• The MMP inhibitor batimastat (BB-94) reduced VEGF release and ascitic fluid formation [14].
• The release of soluble VAP-1 was enhanced by exposure of murine and human adipocytes to TNF-alpha and blocked by batimastat, a metalloprotease inhibitor [15].

Associations of batimastat with other chemical compounds

• The contribution of MMPs to PMN transmigration and lung injury was tested with the MMP inhibitor batimastat (BB-94) in vitro (PMN transmigration across matrigel chambers) and in vivo (myeloperoxidase activity and Evans blue in broncho-alveolar lavage fluid) [16].
• The shedding of HER2 ECD is inhibited by the broad-spectrum metalloprotease inhibitors EDTA, TAPI-2, and batimastat [17].
• Moreover, NT stimulated tyrosine phosphorylation of the EGFR, and pretreatment with a broad spectrum metalloproteinase inhibitor batimastat reduced NT-induced MAP kinase activation [18].
• Release of soluble KIM-1 is enhanced by activating the cells with phorbol 12-myristate 13-acetate and can be inhibited with two metalloproteinase inhibitors, BB-94 (Batimastat) and GM6001 (Ilomastat), suggesting that the cleavage is mediated by a metalloproteinase [19].
• Marimastat and batimastat are potent broad-spectrum inhibitors of all major MMPs and have been shown to prevent or reduce spread and growth of a number of different malignant tumors in numerous animal models [20].

Gene context of batimastat

• This fractalkine-mediated adhesion is further enhanced in the presence of batimastat, indicating that shedding of fractalkine from the cell surface down-regulates the adhesive properties of SMC [21].
• Significantly, the late phase of ERK phosphorylation, detectable within 4 h after exposure, was blocked by the metalloprotease inhibitor batimastat, indicating that autocrine signaling through ligand shedding was responsible for this secondary wave of ERK activity [22].
• When PTH receptor-expressing COS-7 cells were placed in a mixed culture with cells lacking the PTH receptor but expressing a green fluorescent protein-tagged ERK2, stimulation with PTH(1-34) induced phosphorylation of green fluorescent protein-ERK2 that was abolished by either batimastat or tyrphostin AG1478 [23].
• Since the combination of aprotinin and furin convertase inhibitor reduced collagen invasiveness by melanoma cells to a level comparable to that attained with batimastat, we conclude that both MMP-2 and MMP-1 are involved in such tissue invasion [24].
• We have solved the structure of the catalytic domain (cd) of MT3-MMP/MMP-16 in complex with the hydroxamic acid inhibitor batimastat [25].

Analytical, diagnostic and therapeutic context of batimastat

• Intraperitoneal injection of batimastat significantly inhibited the local-regional regrowth of resected MDA-MB-435 tumors in athymic nude mice (in comparison with control mice, P = .035), and it reduced the incidence (P < .05), number (P = .0001), and total volume (P = .0001) of lung metastases [1].
• BACKGROUND: Inhibition of matrix metalloproteinase (MMP) activity after balloon angioplasty by intraperitoneal injection of batimastat reduces late lumen loss by inhibition of constrictive remodeling [26].
• In the lung-invasive tumor model, batimastat administered daily (40 mg/kg i.p.) significantly reduced tumor weight within the lung (72% of vehicle-treated control; P < 0.05) but did not significantly affect nodule number [12].
• Batimastat administered daily, starting at day of tumor transplantation, resulted in a significant growth delay, whereas treatment starting at advanced stage tumor only reduced tumor growth marginally [27].
• The batimastat-collagenase complex is described in detail, and the activities of batimastat analogues are discussed in the light of the protein-inhibitor interactions revealed by the crystallography studies [28].

References