RESUMEN
SDZ 62-434 (CAS 115621-95-9, 5-(4'-piperidinomethylphenyl)-2,3-dihydroimidazo [2,1-a]isoquinoline dihydrochloride), a member of a novel class of antitumor agents, exhibited direct and macrophage-induced cytotoxicity against a variety of murine tumor cell lines. It is more effective than edelfosine in increasing survivors and reducing tumor volume in the oral mouse Meth A fibrosarcoma model. Preliminary studies suggest that an undefined cytotoxic effect, macrophage activation and possible effects on signal transduction may account for its antitumor mechanism of action. SDZ 62-434 is currently in Phase I clinical trials as a potential antitumor agent.
Asunto(s)
Antineoplásicos/farmacología , Imidazoles/farmacología , Isoquinolinas/farmacología , Alantoína/metabolismo , Animales , Antineoplásicos/toxicidad , Broncodilatadores/farmacología , Supervivencia Celular/efectos de los fármacos , Embrión de Pollo , Perros , Ensayos de Selección de Medicamentos Antitumorales , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Cobayas , Hemodinámica/efectos de los fármacos , Hemólisis/efectos de los fármacos , Humanos , Imidazoles/toxicidad , Técnicas In Vitro , Isoquinolinas/toxicidad , Activación de Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos , Trasplante de Neoplasias , Agregación Plaquetaria/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
A piperidine phospholipid ((+/-)-2-[hydroxy] [1-octadecyloxycarbonylpiperidin-3-yl]methoxy-phosphinyl] oxy]-N,N,N, trimethylethaniminium hydroxide inner salt, SDZ 62-826) has been prepared that exhibited weak direct cytotoxicity and strong macrophage-induced cytotoxicity in vitro against a variety of murine and one human tumor cell lines. This compound was found to be as effective as ET-18-OCH3 and SRI 62-834, phospholipids with both strong direct and macrophage-induced cytotoxicity, in increasing survivors and reducing tumor volume when given either orally or intravenously in the mouse MethA fibrosarcoma model. These findings suggest that the macrophage-induced cytotoxicity exhibited by ET-18-OCH3 and other phospholipids may play an important role in this tumor model.