RESUMEN
Autotaxin is an extracellular, two zinc-centered enzyme that hydrolyzes lysophosphatidyl choline to lysophosphatidic acid, involved in various cancerous processes, e.g. migration, proliferation and tumor progression. We examined the autotaxin inhibitory properties of extended structure carbamoylphosphonates (CPOs) PhOC(6)H(4)SO(2)NH(CH(2))nNHCOPO(3)H(2), with increasing lengths of methylene chains, (CH(2))(n), n = 4-8. Carbamoylphosphonates having n = 6, 7, 8 inhibited autotaxin in vitro with IC(50) ≈ 1.5 µM. Using an imaging probe we demonstrated that compound n = 6 inhibits recombinant autotaxin activity in vitro and in vivo, following oral CPO administration. Additionally, daily oral administration of compound n = 7 inhibited over 90% of lung metastases in a murine melanoma metastasis model. Both the carbamoylphosphonates and the enzymes reside and interact in the extracellular space expecting minimal toxic side effects, and presenting a novel approach for inhibiting tumor proliferation and metastasis dissemination.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Melanoma Experimental/tratamiento farmacológico , Organofosfonatos/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Sulfonamidas/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Neoplasias Pulmonares/secundario , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Organofosfonatos/administración & dosificación , Organofosfonatos/química , Relación Estructura-Actividad , Sulfonamidas/administración & dosificación , Sulfonamidas/químicaRESUMEN
cis-2-Aminocyclohexylcarbamoylphosphonic acid ( cis-ACCP) was evaluated in vitro and in two in vivo cancer metastasis models. It reduced metastasis formation in mice by approximately 90% when administered by a repetitive once daily dosing regimen of 50 mg/kg via oral or intraperitoneal routes and was nontoxic up to 500 mg/kg, following intraperitoneal administration daily for two weeks. Pharmacokinetic investigation of cis-ACCP in rats revealed distribution restricted into the extracellular fluid, which is the site of action for the antimetastatic activity and rapid elimination ( t 1/2 approximately 19 min) from blood. Sustained and prolonged absorption ( t 1/2 approximately 126 min) occurred via paracellular mechanism along the small and large intestine with overall bioavailability of 0.3%. The in vivo concentrations of cis-ACCP in the blood in rats was above the minimal concentration for antimetastatic/MMP-inhibitory activity, thus explaining the prolonged action following once daily administration. Finally, 84% of the intravenously administered cis-ACCP to rats was excreted intact in the urine.
Asunto(s)
Antineoplásicos/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz , Organofosfonatos/síntesis química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Cobamidas , Ciclohexanos , Femenino , Humanos , Técnicas In Vitro , Absorción Intestinal , Masculino , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Invasividad Neoplásica , Metástasis de la Neoplasia , Trasplante de Neoplasias , Organofosfonatos/farmacocinética , Organofosfonatos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Ratas , Relación Estructura-Actividad , Distribución Tisular , Pruebas de Toxicidad AgudaRESUMEN
Seven 4-phenoxybenzenesulfonamidopolymethylene carbamoylphosphonates (CPOs) bearing two to eight methylene units in the polymethylene chain were synthesized and evaluated as matrix metalloproteinase (MMP) inhibitors. The five lowest homologues [(CH2)2-6] are selective MMP-2 inhibitors, whereas the two with the longest linkers [(CH2)7,8] lack inhibitory activity. The most potent homologues are those with (CH2)5,6; these two were evaluated for antimetastatic activity in a murine melanoma model and showed good potency both by oral and intraperitoneal administration without any toxic--including musculoskeletal--side effects. In contrast to the previously reported cis-ACCP, which was shown to inhibit MMP-2 for â¼30 min, the new compounds inhibit MMP activity for the duration of measurement, lasting several hours. Pharmacokinetic evaluation revealed, on the one hand, low oral bioavailability; on the other hand, a relatively large calculated volume of distribution, consistent with the observed reversible absorption of CPO 5 to hydroxyapatite, as a model for bone.