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Raffaella Giavazzi - One of the best experts on this subject based on the ideXlab platform.
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matrix metalloproteinases mmp9 and mmp2 induce the release of vascular endothelial growth factor vegf by ovarian carcinoma cells implications for ascites formation
Cancer Research, 2003Co-Authors: Dorina Belotti, Angela Garofalo, Giulia Taraboletti, Paola Paganoni, Luigi Manenti, Sergio Marchini, Raffaella GiavazziAbstract:This study investigated the functional interplay between vascular endothelial growth factor (VEGF) and metalloproteinases (MMPs) in ovarian carcinomas. Levels of MMP9 (pro and activated form) and proMMP2 in ascites correlated with VEGF and with the ascitic volume in nude mice bearing human ovarian carcinoma xenografts (HOC22 and HOC8). The MMP inhibitor Batimastat (BB-94) reduced VEGF release and ascitic fluid formation. Exogenous, activated MMP9, and, to a lesser extent, MMP2, increased VEGF release by SKOV3 and OVCAR3 ovarian carcinoma cells. The effect was dose and time dependent and inhibited by BB-94. MMP9-released VEGF was biologically active, because it induced endothelial cell motility, and its activity was prevented by the VEGF inhibitor SU5416. Our results indicate that MMPs, mainly MMP9, play a role in the release of biologically active VEGF and consequently in the formation of ascites.
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the metalloproteinase inhibitor Batimastat bb 94 causes cell cycle phase perturbations in ovarian cancer cells
Annals of Oncology, 1999Co-Authors: Eugenio Erba, Raffaella Giavazzi, S Ronzoni, L Bassano, M DlncalciAbstract:Matrix metalloproteinases (MMP) are a class of enzymes responsible for matrix degradation. They play a role in metastasis formation by facilitating tumor cell invasion and in angiogenesis by mediating the remodeling and penetretion of extracellular matrix by new capillaries [1, 2]. Therefore a MMP inhibitor should have the potential to block and inhibit tumor progression by preventing local invasion and inhibiting tumor angiogenesis. Batimastat (BB-94) is the first synthetic MMP inhibitor which was investigated in clinic. Preclinically, it has been shown to inhibit metastasis of the murine B16 melanoma [3], reduce the growth of experimental murine hemangioma [4] and the metastatic spread of human colon cancer in nude mice [5]. In nude mice bearing human ovarian carcinoma (HOC) BB-94 reduces ascites and prolongs survival by changing the tumor stromal composition, forming an avascular tumor [6]. Although the preclinical data suggest that BB-94 inhibits extracellular matrix breakdown and neovascularization its antitumor activity might also be due to a direct effect on tumor cell growth. To investigate this, we evaluated whether BB-94 had effected the proliferation and cell cycle phase distribution of Skov-3 human ovarian cancer cells. The clonogenic inhibitory effect of BB-94 on Skov-3 cells was evaluated by a standard clonogenic assay [7]. BB-94, kindly provided by British Biotech Pharmaceuticals Ltd., UK, was dissolved in ethanol. Continuous exposure to 10, 15 or 30 uM for 72 hours inhibited of clonogenicity of Skov-3 cells by about 30%. Shorter exposure times (24 or 48 hours) caused no significant inhibition. Exposure from 96 to 144 h reduced the clonogenicity to about 50% (P < 0.01 Mann-Whitney test). No differences were found between 96-, 120and 144hour treatment (Figure 1). The antiproliferative effect of BB-94 was also confirmed in other human cancer cell lines (e.g., human MOLT-4 leukemia) (data not shown). The cell cycle phase perturbations induced by 10 uM BB-94 were evaluated by biparametric bromodeoxyuridine/DNA (BrdUrd/DNA) flow cytometric analysis [8]. BrdUrd was given to the cells for 48 hours (corresponding to two doubling times of the cells) at different intervals during treatment with BB-94. BB-94 did not affect the incorporation of BrdUrd up to 72-hour treatment. All the BB-94 treated cells were BrdUrd positive and therefore cycling. A small fraction of Go/G! BrdUrd negative cells, about 4% of the whole population, was detected after 96-hour BB-94 treatment. At 144-hour BrdUrd/DNA analysis showed a 50% of BrdUrd-negative cells which were blocked in the Go/G! phase of the cell cycle. Also, the majority of the BrdUrd-positive cells were blocked in the G0/Gi phase of the cell cycle. Most literature on BB-94 focuses on its anti-angiogenetic properties [1, 2, 4, 9]. The present study shows that BB-94 also has some growth inhibitory effects on cancer cells. After prolonged exposure 50% of treated cells were blocked in the Go/Gi phase of the cell cycle. This effect was seen at concentrations achievable in
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Batimastat a synthetic inhibitor of matrix metalloproteinases potentiates the antitumor activity of cisplatin in ovarian carcinoma xenografts
Clinical Cancer Research, 1998Co-Authors: Raffaella Giavazzi, Angela Garofalo, P D Brown, E A Bone, C Ferri, Valeria Lucchini, S Chiari, Maria Ines Nicoletti, Giulia TarabolettiAbstract:Batimastat (also known as BB-94) is a synthetic matrix metalloproteinase inhibitor that has shown antineoplastic and antiangiogenic activity in various tumor models. In this study, two human ovarian carcinoma (HOC) xenografts (HOC22 and HOC8) were used to investigate the effect of Batimastat on the antineoplastic activity of cisplatin. Both xenografts produced ascites and solid lesions in the peritoneal cavity of nude mice. HOC cells were inoculated i.p. in nude mice, and treatment was started at different stages of the disease. Batimastat was administered alone or concurrently with or subsequent to cisplatin therapy. In all of the protocols, the response of HOC xenografts was confirmed by cytological analysis of ascites and histological examination of the organs in the peritoneal cavity. Treatment of nude mice bearing early-stage (3 days after tumor implantation) HOC22 or HOC8 with cisplatin or Batimastat alone delayed tumor growth and increased the survival time of the mice, although all animals eventually died. In contrast, treatment with Batimastat (60 mg/kg i.p. every other day, for a total of eight injections) concomitantly with cisplatin (4 mg/kg i.v., every 7 days for a total of three injections) completely prevented growth and spread of both xenografts, and all animals were alive and healthy on day 200. The potentiation of cisplatin's activity by Batimastat was dose dependent and was observed in the treatment of both advanced (7 days after tumor inoculation) and late-stage (20 days after inoculation) tumor. The administration of Batimastat following cisplatin therapy also led to significant improvement in the survival of mice compared to treatment with cisplatin alone. 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.
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28 o Batimastat potentiates cisplatin activity on humanovarian carcinoma xenografts
European Journal of Cancer, 1996Co-Authors: Maria Ines Nicoletti, P D Brown, Valeria Lucchini, A Garofalo, R Rossi, Raffaella GiavazziAbstract:Batimastat (BB94) is a synthetic metalloproteinase inhibitor with antimetastatic and antiangiogenic activity. We investigated the antineoplastic activity of BB94 in combination with cisplatin (DDP) against human ovarian carcinoma (HOC22) xenografts transplanted ip in nude mice. BB94 (60 mg/kg ip) was given alone, concurrently with or after DDP treatment (4 mg/kg iv) for two weeks. Treatment with BB94 alone on early stage HOC22 increased the survival time of the mice (ILS = 56%), but was not active on late stage tumor. BB94 given concurrently with DDP cured all the mice with early stage H0C22 and increased the survival time of the mice with late stage tumors (ILS=48%). BB94 given after DDP significantly increased the survival of mice (ILS = 162%). Response was assessed by cytohistological analysis and serum CA125. These data show that BB94 is active against human ovarian carcinoma xenografts after initial or concomitant tumor reduction with DDP and provide the rationale for its use with or after reductive chemotherapy.
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inhibition of angiogenesis and murine hemangioma growth by Batimastat a synthetic inhibitor of matrix metalloproteinases
Journal of the National Cancer Institute, 1995Co-Authors: Giulia Taraboletti, Angela Garofalo, Peter D Brown, Dorina Belotti, Teresa Drudis, Patrizia Borsotti, Eugenio Scanziani, Raffaella GiavazziAbstract:Background The importance of matrix metalloproteinases in angiogenesis, tumor growth, and metastasis is well known. However, little is known about the role of matrix metalloproteinases in the formation of hemangiomas and about the possible therapeutic use of matrix metalloproteinase inhibitors in aggressive vascular tumors. 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). 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). The effect of Batimastat was investigated in vitro on endothelial cell proliferation, motility, and invasion of a layer of Matrigel. Results Daily treatment with Batimastat (30, 3, and 0.3 mg/kg at the site of eEnd.1 cell injection) inhibited tumor growth, with increased doubling time. The carboxamide derivative of Batimastat, BB-374, a poor inhibitor of matrix metalloproteinase activity, was less active in reducing hemangioma growth. Histologic analysis of treated tumors indicated a reduction in the size of blood-filled spaces and in hemorrhage. Batimastat also inhibited the angiogenic response induced by cultured eEnd.1 endothelioma cell supernatant embedded in a pellet of Matrigel. Batimastat significantly inhibited endothelial cell invasion in vitro through a layer of Matrigel, but it showed no direct cytotoxic activity. Conclusions Batimastat reduces in vivo growth of experimental hemangiomas, most probably by blocking endothelial cell recruitment by the transformed cells or by interfering with cell organization in vascular structures. Implications These results confirm the importance of matrix metalloproteinase in endothelial cell recruitment that occurs in angiogenesis and in the formation of vascular tumors and suggest a therapeutic potential for synthetic matrix metalloproteinase inhibitors.
Jose Maria Gutierrez - One of the best experts on this subject based on the ideXlab platform.
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skin pathology induced by snake venom metalloproteinase acute damage revascularization and re epithelization in a mouse ear model
Journal of Investigative Dermatology, 2008Co-Authors: Natalia Jimenez, Teresa Escalante, Jose Maria Gutierrez, Alexandra RucavadoAbstract:Viperid snakebite envenomation induces blistering and dermonecrosis. The pathological alterations induced by a snake venom metalloproteinase in the skin were investigated in a mouse ear model. Metalloproteinase BaP1, from Bothrops asper, induced rapid edema, hemorrhage, and blistering; the latter two effects were abrogated by preincubation with the metalloproteinase inhibitor Batimastat. Neutrophils did not play a role in the pathology, as depletion of these cells resulted in a similar histological picture. Blisters are likely to result from the direct proteolytic activity of BaP1 of proteins at the dermal–epidermal junction, probably at the lamina lucida, as revealed by immunostaining for type IV collagen and laminin. Widespread apoptosis of keratinocytes was detected by the TUNEL assay, whereas no apoptosis of capillary endothelial cells was observed. BaP1 induced a drastic reduction in the microvessel density, revealed by immunostaining for the endothelial marker vascular endothelial growth factor receptor-2. This was followed by a rapid angiogenic response, leading to a partial revascularization. Skin damage was followed by inflammation and granulation tissue formation. Then, a successful re-epithelization process occurred, and the skin of the ear regained its normal structure by 2 weeks. Venom metalloproteinase-induced skin damage reproduces the pathological changes described in snakebitten patients.
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effect of the metalloproteinase inhibitor Batimastat in the systemic toxicity induced by bothrops asper snake venom understanding the role of metalloproteinases in envenomation
Toxicon, 2004Co-Authors: Alexandra Rucavado, Teresa Escalante, Jose Maria GutierrezAbstract:Abstract The peptidomimetic hydroxamate metalloproteinase inhibitor Batimastat (BB-94) was assessed for its ability to neutralize the systemic effects (lethality, hemorrhage and coagulopathy) induced by the venom of Bothrops asper , the most important snake from a medical standpoint in Central America. Batimastat inhibited lethality when a venom challenge dose of two LD 50 s was used by intraperitoneal and intravenous routes, with ED 50 s of 250 and 22 μM, respectively. With a challenge dose of three LD 50 s, lethality was not abrogated, but a conspicuous and dose-dependent delay in the time of death was observed in mice injected with mixtures of venom plus Batimastat. Upon incubation with 500 μM Batimastat, venom LD 50 increased 2.86-fold (intraperitoneal route) and 2.37-fold (intravenous route), when compared with LD 50 of venom alone. Batimastat also inhibited the hemorrhagic effect induced by venom in the lungs after intravenous injection. Moreover, Batimastat exerted a significant inhibition of in vitro coagulant and in vivo defibrinogenating effects of venom, evidencing that metalloproteinases play a key role in the coagulopathy characteristic of B. asper envenomation. The remaining uninhibited coagulant effect is due to serine proteinases, i.e. thrombin-like enzymes, since this effect was completely abrogated by the combination of Batimastat and PMSF. Our results stress the view that metalloproteinases play a relevant role in the systemic pathophysiology of B. asper envenomation and that metalloproteinase inhibitors may become a therapeutic alternative in this pathology.
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pulmonary hemorrhage induced by jararhagin a metalloproteinase from bothrops jararaca snake venom
Toxicology and Applied Pharmacology, 2003Co-Authors: Teresa Escalante, Alexandra Rucavado, Javier Nunez, Ana Maria Moura Da Silva, David R G Theakston, Jose Maria GutierrezAbstract:Abstract Jararhagin is the most important hemorrhagic component in the venom of the snake Bothrops jararaca, a species of medical importance in South America. It is a P-III zinc-dependent metalloproteinase comprising catalytic, disintegrin-like, and cysteine-rich domains. Jararhagin injected intravenously into mice induced rapid and prominent bleeding in the lungs, whereas other organs were devoid of overt hemorrhagic manifestations. This action depends on the proteolytic activity of jararhagin, since it was abrogated by the synthetic inhibitor Batimastat. There were conspicuous ultrastructural alterations in cells at the alveolo-capillary unit, i.e., capillary endothelial cells and type I pneumocytes, with a characteristic pattern of “regional alveolar damage” associated with extravasation. These pathological effects were observed under conditions in which the whole blood clotting time, bleeding time, and fibrinogen levels were not affected. 125 I-labeled jararhagin is concentrated mainly in liver and kidneys after iv injection, with little radioactivity observed in the lungs, thereby indicating that the predominance of pulmonary microvascular damage is not due to a preferential concentration of this enzyme in the lungs. Despite the fact that jararhagin is complexed by plasma proteins after iv injection, its hemorrhagic activity was not inhibited by the plasma proteinase inhibitor α 2 -macroglobulin, and was only partially reduced by normal mouse serum, suggesting that resistance to inhibition may contribute to its ability to cause pulmonary hemorrhage.
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inhibition of local hemorrhage and dermonecrosis induced by bothrops asper snake venom effectiveness of early in situ administration of the peptidomimetic metalloproteinase inhibitor Batimastat and the chelating agent cana2edta
American Journal of Tropical Medicine and Hygiene, 2000Co-Authors: Alexandra Rucavado, Teresa Escalante, Aida Franceschi, Fernando Chaves, Guillermo Leon, Yara Cury, Michael Ovadia, Jose Maria GutierrezAbstract:The effectiveness of the chelating agent CaNa2EDTA and the peptidomimetic matrix metalloproteinase inhibitor Batimastat (BB-94) to inhibit local tissue damage induced by Bothrops asper snake venom was studied in mice. Both compounds totally inhibited proteolytic, hemorrhagic, and dermonecrotic effects, and partially reduced edema-forming activity, when incubated with venom prior to injection. Much lower concentrations of Batimastat than of CaNa2EDTA were required to inhibit these effects. In addition, Batimastat, but not CaNa2EDTA, partially reduced myotoxic activity of the venom. When the inhibitors were administered at various time intervals after envenomation at the same site of venom injection, both compounds were effective in neutralizing local hemorrhage and dermonecrosis if administered rapidly after venom. Inhibition was not as effective as the time lapse between venom and inhibitor injections increased. Owing to the relevance of metalloproteinases in the pathogenesis of local tissue damage induced by B. asper and other pit viper venoms, it is suggested that administration of peptidomimetic metalloproteinase inhibitors or CaNa2EDTA at the site of venom injection may represent a useful alternative to complement antivenoms in the neutralization of venom-induced local tissue damage.
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effectiveness of Batimastat a synthetic inhibitor of matrix metalloproteinases in neutralizing local tissue damage induced by bap1 a hemorrhagic metalloproteinase from the venom of the snake bothrops asper
Biochemical Pharmacology, 2000Co-Authors: Teresa Escalante, Alexandra Rucavado, Aida Franceschi, Jose Maria GutierrezAbstract:Batimastat (BB-94), a synthetic hydroxamate peptidomimetic matrix metalloproteinase inhibitor, was tested for its ability to inhibit proteolytic and toxic effects induced by BaP1, a 24-kDa hemorrhagic metalloproteinase isolated from the venom of Bothrops asper, the medically most important snake species in Central America and southern Mexico. Batimastat inhibited proteolytic activity on biotinylated casein, with anIC(50) of 80 nM. In addition, Batimastat was effective in inhibiting hemorrhagic, dermonecrotic, and edema-forming activities of this metalloproteinase if incubated with the enzyme prior to the assays. When the inhibitor was administered i.m. at the site of the toxin injection without preincubation, rapidly after metalloproteinase administration, it totally abrogated the hemorrhagic and dermonecrotic effects of BaP1. Inhibition was less effective as the time lapse between toxin and Batimastat injection increased, due to the extremely rapid development of BaP1-induced local tissue damage in this experimental model. On the other hand, Batimastat was ineffective if administered by the i.p. route immediately after toxin injection. It is concluded that Batimastat, and probably other synthetic metalloproteinase inhibitors, may become useful therapeutic tools aimed at the in situ inhibition of venom metalloproteinases, when injected at the site of the bite rapidly after envenomation.
Alexandra Rucavado - One of the best experts on this subject based on the ideXlab platform.
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skin pathology induced by snake venom metalloproteinase acute damage revascularization and re epithelization in a mouse ear model
Journal of Investigative Dermatology, 2008Co-Authors: Natalia Jimenez, Teresa Escalante, Jose Maria Gutierrez, Alexandra RucavadoAbstract:Viperid snakebite envenomation induces blistering and dermonecrosis. The pathological alterations induced by a snake venom metalloproteinase in the skin were investigated in a mouse ear model. Metalloproteinase BaP1, from Bothrops asper, induced rapid edema, hemorrhage, and blistering; the latter two effects were abrogated by preincubation with the metalloproteinase inhibitor Batimastat. Neutrophils did not play a role in the pathology, as depletion of these cells resulted in a similar histological picture. Blisters are likely to result from the direct proteolytic activity of BaP1 of proteins at the dermal–epidermal junction, probably at the lamina lucida, as revealed by immunostaining for type IV collagen and laminin. Widespread apoptosis of keratinocytes was detected by the TUNEL assay, whereas no apoptosis of capillary endothelial cells was observed. BaP1 induced a drastic reduction in the microvessel density, revealed by immunostaining for the endothelial marker vascular endothelial growth factor receptor-2. This was followed by a rapid angiogenic response, leading to a partial revascularization. Skin damage was followed by inflammation and granulation tissue formation. Then, a successful re-epithelization process occurred, and the skin of the ear regained its normal structure by 2 weeks. Venom metalloproteinase-induced skin damage reproduces the pathological changes described in snakebitten patients.
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effect of the metalloproteinase inhibitor Batimastat in the systemic toxicity induced by bothrops asper snake venom understanding the role of metalloproteinases in envenomation
Toxicon, 2004Co-Authors: Alexandra Rucavado, Teresa Escalante, Jose Maria GutierrezAbstract:Abstract The peptidomimetic hydroxamate metalloproteinase inhibitor Batimastat (BB-94) was assessed for its ability to neutralize the systemic effects (lethality, hemorrhage and coagulopathy) induced by the venom of Bothrops asper , the most important snake from a medical standpoint in Central America. Batimastat inhibited lethality when a venom challenge dose of two LD 50 s was used by intraperitoneal and intravenous routes, with ED 50 s of 250 and 22 μM, respectively. With a challenge dose of three LD 50 s, lethality was not abrogated, but a conspicuous and dose-dependent delay in the time of death was observed in mice injected with mixtures of venom plus Batimastat. Upon incubation with 500 μM Batimastat, venom LD 50 increased 2.86-fold (intraperitoneal route) and 2.37-fold (intravenous route), when compared with LD 50 of venom alone. Batimastat also inhibited the hemorrhagic effect induced by venom in the lungs after intravenous injection. Moreover, Batimastat exerted a significant inhibition of in vitro coagulant and in vivo defibrinogenating effects of venom, evidencing that metalloproteinases play a key role in the coagulopathy characteristic of B. asper envenomation. The remaining uninhibited coagulant effect is due to serine proteinases, i.e. thrombin-like enzymes, since this effect was completely abrogated by the combination of Batimastat and PMSF. Our results stress the view that metalloproteinases play a relevant role in the systemic pathophysiology of B. asper envenomation and that metalloproteinase inhibitors may become a therapeutic alternative in this pathology.
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pulmonary hemorrhage induced by jararhagin a metalloproteinase from bothrops jararaca snake venom
Toxicology and Applied Pharmacology, 2003Co-Authors: Teresa Escalante, Alexandra Rucavado, Javier Nunez, Ana Maria Moura Da Silva, David R G Theakston, Jose Maria GutierrezAbstract:Abstract Jararhagin is the most important hemorrhagic component in the venom of the snake Bothrops jararaca, a species of medical importance in South America. It is a P-III zinc-dependent metalloproteinase comprising catalytic, disintegrin-like, and cysteine-rich domains. Jararhagin injected intravenously into mice induced rapid and prominent bleeding in the lungs, whereas other organs were devoid of overt hemorrhagic manifestations. This action depends on the proteolytic activity of jararhagin, since it was abrogated by the synthetic inhibitor Batimastat. There were conspicuous ultrastructural alterations in cells at the alveolo-capillary unit, i.e., capillary endothelial cells and type I pneumocytes, with a characteristic pattern of “regional alveolar damage” associated with extravasation. These pathological effects were observed under conditions in which the whole blood clotting time, bleeding time, and fibrinogen levels were not affected. 125 I-labeled jararhagin is concentrated mainly in liver and kidneys after iv injection, with little radioactivity observed in the lungs, thereby indicating that the predominance of pulmonary microvascular damage is not due to a preferential concentration of this enzyme in the lungs. Despite the fact that jararhagin is complexed by plasma proteins after iv injection, its hemorrhagic activity was not inhibited by the plasma proteinase inhibitor α 2 -macroglobulin, and was only partially reduced by normal mouse serum, suggesting that resistance to inhibition may contribute to its ability to cause pulmonary hemorrhage.
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inhibition of local hemorrhage and dermonecrosis induced by bothrops asper snake venom effectiveness of early in situ administration of the peptidomimetic metalloproteinase inhibitor Batimastat and the chelating agent cana2edta
American Journal of Tropical Medicine and Hygiene, 2000Co-Authors: Alexandra Rucavado, Teresa Escalante, Aida Franceschi, Fernando Chaves, Guillermo Leon, Yara Cury, Michael Ovadia, Jose Maria GutierrezAbstract:The effectiveness of the chelating agent CaNa2EDTA and the peptidomimetic matrix metalloproteinase inhibitor Batimastat (BB-94) to inhibit local tissue damage induced by Bothrops asper snake venom was studied in mice. Both compounds totally inhibited proteolytic, hemorrhagic, and dermonecrotic effects, and partially reduced edema-forming activity, when incubated with venom prior to injection. Much lower concentrations of Batimastat than of CaNa2EDTA were required to inhibit these effects. In addition, Batimastat, but not CaNa2EDTA, partially reduced myotoxic activity of the venom. When the inhibitors were administered at various time intervals after envenomation at the same site of venom injection, both compounds were effective in neutralizing local hemorrhage and dermonecrosis if administered rapidly after venom. Inhibition was not as effective as the time lapse between venom and inhibitor injections increased. Owing to the relevance of metalloproteinases in the pathogenesis of local tissue damage induced by B. asper and other pit viper venoms, it is suggested that administration of peptidomimetic metalloproteinase inhibitors or CaNa2EDTA at the site of venom injection may represent a useful alternative to complement antivenoms in the neutralization of venom-induced local tissue damage.
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effectiveness of Batimastat a synthetic inhibitor of matrix metalloproteinases in neutralizing local tissue damage induced by bap1 a hemorrhagic metalloproteinase from the venom of the snake bothrops asper
Biochemical Pharmacology, 2000Co-Authors: Teresa Escalante, Alexandra Rucavado, Aida Franceschi, Jose Maria GutierrezAbstract:Batimastat (BB-94), a synthetic hydroxamate peptidomimetic matrix metalloproteinase inhibitor, was tested for its ability to inhibit proteolytic and toxic effects induced by BaP1, a 24-kDa hemorrhagic metalloproteinase isolated from the venom of Bothrops asper, the medically most important snake species in Central America and southern Mexico. Batimastat inhibited proteolytic activity on biotinylated casein, with anIC(50) of 80 nM. In addition, Batimastat was effective in inhibiting hemorrhagic, dermonecrotic, and edema-forming activities of this metalloproteinase if incubated with the enzyme prior to the assays. When the inhibitor was administered i.m. at the site of the toxin injection without preincubation, rapidly after metalloproteinase administration, it totally abrogated the hemorrhagic and dermonecrotic effects of BaP1. Inhibition was less effective as the time lapse between toxin and Batimastat injection increased, due to the extremely rapid development of BaP1-induced local tissue damage in this experimental model. On the other hand, Batimastat was ineffective if administered by the i.p. route immediately after toxin injection. It is concluded that Batimastat, and probably other synthetic metalloproteinase inhibitors, may become useful therapeutic tools aimed at the in situ inhibition of venom metalloproteinases, when injected at the site of the bite rapidly after envenomation.
Robert B Dickson - One of the best experts on this subject based on the ideXlab platform.
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increased stromal expression of murine urokinase plasminogen activator in a human breast cancer xenograft model following treatment with the matrix metalloprotease inhibitor Batimastat
Breast Cancer Research and Treatment, 2001Co-Authors: Claus Holsthansen, Jennifer A Low, Ross W Stephens, Michael D Johnson, Peter Carmeliet, Thomas Leth Frandsen, Nils Brunner, Robert B DicksonAbstract:The matrix metalloprotease (MMP) family of enzymes and the urokinase plasminogen activator (uPA) pathway have both been implicated in tumor invasion and metastasis and in poor prognosis of cancer. We have previously shown that treatment with Batimastat, a synthetic MMP inhibitor, leads to significant retardation but not regression of tumor growth in a human breast cancer xenograft model. In addition, Batimastat treatment did not inhibit local tumor invasion, nor did it encourage stromal encapsulation of the tumor, suggesting the additional involvement of non-MMP proteolytic mechanisms. To investigate the presence of an alternative extracellular matrix protease whose activity is known to be important in breast cancer, but which is not inhibited by Batimastat, expression of murine and human uPA were examined by in situ hybridization and ELISA. No differences were observed between untreated and Batimastat-treated tumors regarding human uPA mRNA and protein. In contrast, murine uPA mRNA expression was increased at the tumor-stromal junction in Batimastat-treated tumors in comparison with the control tumors. In agreement with these results, Batimastat treatment was shown to significantly induce murine uPA protein content in the tumors. Inoculating MDA435/LCC-6 cells into immunodeficient, uPA-deficient mice resulted in tumor growth retardation as compared to tumor growth in littermate wild-type controls, while addition of Batimastat treatment to uPA-/- mice did not result in further growth inhibition. The increased expression of stromal uPA may represent a cellular response to MMP inhibition and may demonstrate a new level of plasticity in the malignant progression of the disease. These results may have important implications for the clinical applications of MMP inhibitors, as well as for development of other anti-invasion drugs.
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the matrix metalloproteinase inhibitor Batimastat bb 94 retards human breast cancer solid tumor growth but not ascites formation in nude mice
Clinical Cancer Research, 1996Co-Authors: J A Low, Mark D Johnson, E A Bone, Robert B DicksonAbstract:Matrix metalloproteinases (MMPs) are thought to play a significant role in tumor invasion and metastasis as well as angiogenesis. Batimastat, also known as BB-94, acts as an inhibitor of metalloproteinase activity by binding the zinc ion in the active site of MMPs. In our study, the hormone-independent MDA435/LCC6 human breast cancer cell line was used to seed solid tumors s.c. into the region of the mammary fat pad in athymic nude mice. Mice were treated with 50 mg/kg Batimastat i.p. Tumor volume measurements showed a statistically significant decrease in tumor size between Batimastat-treated and control animals. In contrast, we also used the same MDA435/LCC6 cell line to propagate a malignant ascites in nude mice, which yielded a very different response to Batimastat. Batimastat, in previously published literature, had been shown to prolong the life of mice bearing ovarian ascites tumors. Treatment with Batimastat in our ascites model produced no increase in survival or significant suppression of ascites formation. However, treated animals showed dramatic tumor cell consolidation and less dispersed ascites cells compared with control animals. Two potential targets of Batimastat, gelatinase A and B (MMP-2 and -9, respectively), were examined in both tumor sites. These metalloproteinases were present in both solid tumor and ascites fluid and in both cases were host derived and not produced by the tumor. We conclude that Batimastat may have different effects on tumor progression and growth depending on the site of tumor implantation.
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phase i trial of a novel matrix metalloproteinase inhibitor Batimastat bb 94 in patients with advanced cancer
Investigational New Drugs, 1996Co-Authors: Slawomir Wojtowiczpraga, Robert B Dickson, Jennifer Low, John L Marshall, Elizabeth Ness, James F Barter, Mark Sale, Peter Mccann, Jeff Moore, Alice ColeAbstract:Degradation of basement membrane and extracellular matrix by matrix metalloproteinases (MMPs) is believed to be required for tumor invasion, tumor-induced angiogenesis and vascular invasion. A synthetic hydroxamate, Batimastat (also known as BB-94), inhibits MMPs by binding the zinc ion in the active site of the MMP. Batimastat inhibits at least 50% of MMP activity at concentrations less than or equal to 10 ng/ml in vitro. Batimastat retarded ascites accumulation and increased survival in mice with human ovarian tumor xenografts. Acute and long-term toxicological studies revealed no major toxicity in animals. Batimastat is poorly soluble and was administered intraperitoneally (i.p.) as a suspension. Previous studies in patients with malignant ascites have shown no major toxicities at doses as high as 1350 mg/m2.
Peter D Brown - One of the best experts on this subject based on the ideXlab platform.
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control of lymphatic and hematogenous metastasis of a rat mammary carcinoma by the matrix metalloproteinase inhibitor Batimastat bb 94
Cancer Research, 1996Co-Authors: Suzanne A Eccles, Gary Box, William Court, Elisabeth A Bone, Wayne Thomas, Peter D BrownAbstract:We examined the effects of the synthetic matrix metalloproteinase inhibitor Batimastat (BB-94) on lung colonization and spontaneous metastasis of a rat mammary carcinoma, HOSP.1P. This tumor expresses both latent and active forms of the matrix metalloproteinases MMP-2 and MMP-9, although the former, as in human breast cancer, is the most prominent. Administration of Batimastat (6 x 30 mg/kg i.p.) inhibited by up to 80% both the number and median weights of HOSP.1P lung colonies following i.v. inoculation of cells. This implies an effect both on seeding efficiency and subsequent tumor development. In spontaneous metastasis assays, limited treatment with Batimastat (commencing when s.c. tumors were established and continuing until 5 or 14 days after their surgical removal) significantly inhibited lung metastasis but had little effect on lymphatic metastasis. However, when treatment was initiated 2 days prior to surgery and continued until day 70, 100% of animals survived to day 120 when there was no evidence of metastatic disease. All control animals (n = 25) in two separate experiments died before day 100 with lymphatic, lung, and extrapulmonary metastases. 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.
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inhibition of organ invasion by the matrix metalloproteinase inhibitor Batimastat bb 94 in two human colon carcinoma metastasis models
Cancer Research, 1995Co-Authors: Susan A Watson, M J Crimmin, Peter D Brown, Teresa M Morris, Graham Robinson, J D HardcastleAbstract:Abstract The effect of the matrix metalloproteinase inhibitor Batimastat was evaluated in two human colorectal cancer metastasis models involving: ( a ) the liver-invasive tumor C170HM 2 and ( b ) the lung-invasive tumor AP5LV, both of which have been shown to express the M r 72,000 type IV collagenase. Batimastat at concentrations between 0.01 and 3.0 µg/ml had no direct cytotoxic effects on the in vitro growth of the cell lines. In the liver-invasive tumor model, Batimastat administered i.p. from day 10 to termination of the therapy (day 39) at 40 mg/kg reduced both the mean number of liver tumors (35% of vehicle-treated control; P P P
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inhibition of angiogenesis and murine hemangioma growth by Batimastat a synthetic inhibitor of matrix metalloproteinases
Journal of the National Cancer Institute, 1995Co-Authors: Giulia Taraboletti, Angela Garofalo, Peter D Brown, Dorina Belotti, Teresa Drudis, Patrizia Borsotti, Eugenio Scanziani, Raffaella GiavazziAbstract:Background The importance of matrix metalloproteinases in angiogenesis, tumor growth, and metastasis is well known. However, little is known about the role of matrix metalloproteinases in the formation of hemangiomas and about the possible therapeutic use of matrix metalloproteinase inhibitors in aggressive vascular tumors. 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). 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). The effect of Batimastat was investigated in vitro on endothelial cell proliferation, motility, and invasion of a layer of Matrigel. Results Daily treatment with Batimastat (30, 3, and 0.3 mg/kg at the site of eEnd.1 cell injection) inhibited tumor growth, with increased doubling time. The carboxamide derivative of Batimastat, BB-374, a poor inhibitor of matrix metalloproteinase activity, was less active in reducing hemangioma growth. Histologic analysis of treated tumors indicated a reduction in the size of blood-filled spaces and in hemorrhage. Batimastat also inhibited the angiogenic response induced by cultured eEnd.1 endothelioma cell supernatant embedded in a pellet of Matrigel. Batimastat significantly inhibited endothelial cell invasion in vitro through a layer of Matrigel, but it showed no direct cytotoxic activity. Conclusions Batimastat reduces in vivo growth of experimental hemangiomas, most probably by blocking endothelial cell recruitment by the transformed cells or by interfering with cell organization in vascular structures. Implications These results confirm the importance of matrix metalloproteinase in endothelial cell recruitment that occurs in angiogenesis and in the formation of vascular tumors and suggest a therapeutic potential for synthetic matrix metalloproteinase inhibitors.
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inhibition of the metastatic spread and growth of b16 bl6 murine melanoma by a synthetic matrix metalloproteinase inhibitor
International Journal of Cancer, 1994Co-Authors: Renato G S Chirivi, Angela Garofalo, M J Crimmin, Lindsay Bawden, Antonella Stoppacciaro, Peter D Brown, Raffaella GiavazziAbstract:The synthetic matrix metalloproteinase inhibitor Batimastat was tested for its ability to inhibit growth and metastatic spread of the B16-BL6 murine melanoma in syngeneic C57BL/6N mice. Intraperitoneal administration of Batimastat resulted in a significant inhibition in the number of lung colonies produced by B16-BL6 cells injected i.v. The effect of Batimastat on spontaneous metastases was examined in mice inoculated in the hind footpad with B16-BL6 melanoma. The primary tumor was removed surgically after 26-28 days. Batimastat was administered twice a day from day 14 to day 28 (pre-surgery) or from day 26 to day 44 (post-surgery). With both protocols, the median number of lung metastases was not significantly affected, but there was a significant reduction in the weight of the metastases. Finally, the effect of Batimastat was examined on s.c. growth of B16-BL6 melanoma. 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. Our results indicate that a matrix metalloproteinase inhibitor can not only prevent the colonization of secondary organs by B16-BL6 cells but also limit the growth of solid tumors.
