ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Imidazoles/pharmacology , Isoquinolines/pharmacology , Allantoin/metabolism , Animals , Antineoplastic Agents/toxicity , Bronchodilator Agents/pharmacology , Cell Survival/drug effects , Chick Embryo , Dogs , Drug Screening Assays, Antitumor , Fibroblasts/drug effects , Fibroblasts/metabolism , Guinea Pigs , Hemodynamics/drug effects , Hemolysis/drug effects , Humans , Imidazoles/toxicity , In Vitro Techniques , Isoquinolines/toxicity , Macrophage Activation/drug effects , Male , Mice , Mice, Inbred Strains , Neoplasm Transplantation , Platelet Aggregation/drug effects , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , Tumor Cells, CulturedABSTRACT
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.
