RESUMEN
To determine the ocular pharmacokinetics, physiological and histological effects of prinomastat (a matrix metalloprotease inhibitor), a total of seventy-seven eyes of New Zealand White rabbits received intravitreous and subtenon injections of prinomastat or of acidified water vehicle as control, Doses of 0.5 mg in 0.05 mL of prinomastat or acidified water were used for intravitreal injection. For the subtenon injections, doses of 5 mg prinomastat in 0.5 mL of acidified water were administered in the superotemporal quadrant. Intraocular pharmacokinetics were determined by analyzing vitreous samples at different postinjection time points using Liquid Chromatography-Mass Spectroscopy/Mass Spectroscopy (LC-MS/MS). The toxicity was evaluated by biomicroscopy, electroretinography (ERG), pneumatonometry, and histology. No toxicity was found with either administration method. At day 14 after intravitreal injection, levels of prinomastat in the vitreous and choroid were 1.4 ng/mg and 7.8 ng/mg, respectively. The retinal levels of prinomastat were 22 ng/mg at 24 hr and dropped below 1 ng/mg at 48 hr. Prinomastat remained well above minimum effective concentration in the choroid for at least four weeks after a single intravitreal injection, suggesting that local intravitreal injection may have potential in treating choroidal neovascularization.
Asunto(s)
Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/toxicidad , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidad , Metaloendopeptidasas/antagonistas & inhibidores , Compuestos Orgánicos , Retina/metabolismo , Cuerpo Vítreo/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Evaluación Preclínica de Medicamentos , Electrorretinografía/efectos de los fármacos , Cromatografía de Gases y Espectrometría de Masas , Presión Intraocular/efectos de los fármacos , Conejos , Retina/efectos de los fármacos , Tonometría Ocular , Cuerpo Vítreo/efectos de los fármacosRESUMEN
PURPOSE: To determine the efficacy of prinomastat (AG3340), a synthetic inhibitor of matrix metalloproteinase, in the treatment of experimental proliferative vitreoretinopathy (PVR) induced by intravitreal dispase injection. METHODS: One eye each of 53 New Zealand white rabbits was injected in the vitreous cavity with 0.07 unit of dispase to induce PVR. One week after PVR induction, 53 rabbits were randomized (27:26) to receive 0.5 mg prinomastat or the vehicle of the drug (acidified water) intravitreally every two weeks. The scores of PVR severity (scale of 1-5) were graded to compare the prinomastat-treated animals with the control group. RESULTS: The average PVR scores in the treatment and control groups were 2.62 and 3.57 respectively (p = 0.038; Wilcoxon rank sum). Clinically significant PVR with retinal detachment (PVR > or = grade 3) developed in 76% of rabbits in the control group versus 51% of rabbits treated with prinomastat. CONCLUSIONS: Intravitreally administered prinomastat decreased development of PVR in an experimental model which made use of dispase to induce PVR.
Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Inhibidores de la Metaloproteinasa de la Matriz , Compuestos Orgánicos , Vitreorretinopatía Proliferativa/tratamiento farmacológico , Animales , Evaluación Preclínica de Medicamentos , Membrana Epirretinal/patología , Femenino , Fondo de Ojo , Masculino , Conejos , Retina/efectos de los fármacos , Retina/patología , Vitreorretinopatía Proliferativa/patologíaRESUMEN
Effective therapy is needed to improve the survival of patients with advanced lung cancers. We studied the effects of a selective metalloprotease inhibitor, AG3340, on chemoresistant human non-small cell lung cancer tumors (line MV522) in vivo. Mice bearing s.c. tumors were given twice-daily oral doses of AG3340. As a single agent, AG3340 inhibited angiogenesis (up to 77%) and tumor growth (up to 65%) in a dose-dependent manner at well-tolerated daily doses up to 400 mg/kg/day and induced significant tumor necrosis. In contrast, tumors were relatively insensitive to carboplatin with approximately 25% growth inhibition observed at a maximum tolerated dose of approximately 30 mg/kg/week (given i.p., twice weekly). Carboplatin inhibited tumor growth markedly only at toxic doses, demonstrating a superior therapeutic index of AG3340 to carboplatin in this tumor model. A suboptimal dose of AG3340, when used in combination with an ineffective maximum tolerated dose of carboplatin, resulted in greater tumor growth inhibitions than those produced by either agent alone. Similarly, growth inhibition was enhanced when AG3340 was used in combination with paclitaxel. Cotreatment with carboplatin did not alter AG3340 plasma concentrations achieved acutely after oral dosing. These data demonstrate an antiangiogenic and antitumor effect of AG3340 when used as a single agent and enhanced growth inhibitions when AG3340 is used in combination with cytotoxic agents. These data suggest that treatment with this novel matrix metalloprotease inhibitor may be beneficial in advanced lung cancers and other chemoresistant malignancies.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos Orgánicos , Animales , Antineoplásicos/sangre , Antineoplásicos/toxicidad , Antineoplásicos Fitogénicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Carboplatino/administración & dosificación , Carboplatino/toxicidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Resistencia a Antineoplásicos , Quimioterapia Combinada , Femenino , Humanos , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Neovascularización Patológica , Paclitaxel/administración & dosificación , Trasplante Heterólogo , Resultado del Tratamiento , Células Tumorales CultivadasRESUMEN
We studied AG3340, a potent metalloproteinase (MMP) inhibitor with pM affinities for inhibiting gelatinases (MMP-2 and -9), MT-MMP-1 (MMP-14), and collagenase-3 (MMP-13) in many tumor models. AG3340 produced dose-dependent pharmacokinetics and was well tolerated after intraperitoneal (i.p.) and oral dosing in mice. Across human tumor models, AG3340 produced profound tumor growth delays when dosing began early or late after tumor implantation, although all established tumor types did not respond to AG3340. A dose-response relationship was explored in three models: COLO-320DM colon, MV522 lung, and MDA-MB-435 breast. Dose-dependent inhibitions of tumor growth (over 12.5-200 mg/kg given twice daily, b.i.d.) were observed in the colon and lung models; and in a third (breast), maximal inhibitions were produced by the lowest dose of AG3340 (50 mg/kg, b.i.d.) that was tested. In another model, AG3340 (100 mg/kg, once daily, i.p.) markedly inhibited U87 glioma growth and increased animal survival. AG3340 also inhibited tumor growth and increased the survival of nude mice bearing androgen-independent PC-3 prostatic tumors. In a sixth model, KKLS gastric, AG3340 did not inhibit tumor growth but potentiated the efficacy of Taxol. Importantly, AG3340 markedly decreased tumor angiogenesis (as assessed by CD-31 staining) and cell proliferation (as assessed by bromodeoxyuridine incorporation), and increased tumor necrosis and apoptosis (as assessed by hematoxylin and eosin and TUNEL staining). These effects were model dependent, but angiogenesis was commonly inhibited. AG3340 had a superior therapeutic index to the cytotoxic agents, carboplatin and Taxol, in the MV522 lung cancer model. In combination, AG3340 enhanced the efficacy of these cytotoxic agents without altering drug tolerance. Additionally, AG3340 decreased the number of murine melanoma (B16-F10) lesions arising in the lung in an intravenous metastasis model when given in combination with carboplatin or Taxol. These studies directly support the use of AG3340 in front-line combination chemotherapy in ongoing clinical trials in patients with advanced malignancies of the lung and prostate.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Glioma/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Metaloendopeptidasas/antagonistas & inhibidores , Neovascularización Patológica/prevención & control , Compuestos Orgánicos , Animales , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/patología , División Celular/efectos de los fármacos , Línea Celular , Neoplasias del Colon/irrigación sanguínea , Neoplasias del Colon/patología , Femenino , Glioma/patología , Humanos , Cinética , Neoplasias Pulmonares/irrigación sanguínea , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Ratones SCID , Inhibidores de Proteasas/uso terapéutico , Trasplante HeterólogoRESUMEN
Chronic rejection is one of the principal factors that lead to development of obliterative bronchiolitis, which is the cause of death for 50% of lung allograft recipients. To more fully comprehend the pathogenesis of chronic rejection, we investigated the expression of endothelin-1 (ET-1) and endothelin-converting enzyme-1 (ECE-1) in inadequately immuno-suppressed rat lung allografts (n = 15) at monthly intervals after transplantation and compared these findings with those in normal rat lung (n = 5), using immunohistochemistry. Throughout the posttransplantation period, inflammatory cells expressed weak to moderate immunoexpression for both peptides. Constant weak to moderate immunoexpression for both peptides was also seen in the alveolar epithelium and neovascularized endothelium. Early after transplantation the vascular endothelium demonstrated strong immunostaining compared with control sections. This immunostaining, however, was reduced to control levels at later stages of rejection. As rejection progressed, staining in the airway epithelium diminished to weak levels as compared with that in controls. These findings suggest a causal role for ET-1 and ECE-1 in the inflammatory and proliferative damage associated with chronic rejection after lung transplantation.
Asunto(s)
Ácido Aspártico Endopeptidasas/metabolismo , Endotelina-1/metabolismo , Pulmón/enzimología , Metaloendopeptidasas/metabolismo , Animales , Líquido del Lavado Bronquioalveolar , Endotelina-1/sangre , Enzimas Convertidoras de Endotelina , Inmunohistoquímica , Terapia de Inmunosupresión , Trasplante de Pulmón/fisiología , Masculino , Ratas , Ratas Endogámicas BN , Ratas Endogámicas LewRESUMEN
Matrix metalloproteinases are a family of zinc-containing proteases that degrade extracellular matrix and basement membranes. These enzymes are thought to play a role in processes essential for tumor growth, invasion, and metastasis. Here we report pharmacokinetic and anti-tumor efficacy studies with a series of structurally related inhibitors of these enzymes that were synthesized at Agouron Pharmaceuticals using protein structure based drug design. The compounds studied were AG3287, AG3293, AG3294, AG3296, AG3319, and AG3340. Rat oral bioavailability ranged from 15 to 68%. Despite similar profiles of enzyme inhibition across the family of enzymes, and similar pharmacokinetics following i.p. administration to mice, efficacy against the Lewis lung carcinoma murine model varied from tumor growth enhancement, to significant reductions in the size of primary tumors and the number of lung metastases. AG3340 was the most efficacious compound against the Lewis lung carcinoma model, resulting in the complete cessation of primary tumor growth throughout the experiment in 4/6 mice treated with daily i.p. injections at a dose of 50 mg/kg. This treatment inhibited the formation of lung metastases greater than 5 mm in diameter by 90%.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Metaloendopeptidasas/antagonistas & inhibidores , Compuestos Orgánicos , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/sangre , Inhibidores Enzimáticos/farmacocinética , Semivida , Melanoma Experimental/tratamiento farmacológico , Ratones , Ratas , Solubilidad , Relación Estructura-ActividadRESUMEN
BACKGROUND: Obliterative bronchiolitis (OB) is a disease affecting a large percentage of lung and heart-lung transplant recipients. Histologically, the disease is characterized by inflammation, cellular proliferation, and obliteration of terminal airways. METHODS: We investigated the production of inducible and constitutive nitric oxide synthases and peroxynitrite by immunohistochemistry in the lungs of control subjects (n=14) compared with those of transplant recipients with OB (n=8). RESULTS: Strong immunoreactivity for inducible nitric oxide synthase and nitrotyrosine, a marker of protein nitration by peroxynitrite, was seen in inflammatory cells, airway epithelium, and vascular endothelium of patients with OB, compared with little immunoreactivity in control lungs. Immunoreactivity for constitutive nitric oxide synthase was abundant in the airway epithelium and vascular endothelium of control lungs, however, it was decreased in airway epithelial cells and arterial endothelial cells of patients with OB. CONCLUSIONS: We conclude that increased formation of the potent oxidant peroxynitrite and decreased production of endothelial nitric oxide may contribute to the functional and morphological abnormalities of OB.