ENHANCEMENT OF RICIN TOXIN-A CHAIN IMMUNOTOXIN ACTIVITY - SYNTHESIS, IONOPHORETIC ABILITY, AND IN-VITRO ACTIVITY OF MONENSIN DERIVATIVES

Site selective toxin delivery was achieved by coupling monoclonal anti body to the A chain subunit of ricin (RTA-IT). The cell killing potenc y of RTA-IT can be drastically increased in vitro by using ionophores such as monensin. To reduce the intrinsic toxicity of monensin and to enhance its in vitro and in vivo activity, we synthesized 7 derivative s characterized by different lipophilicities. These derivatives were a lso analyzed for ionophoretic activity on intact cells, toxicity, and RTA-IT-enhancing activity. Two different RTA-IT were assayed on a huma n leukemia cell line. A correlation between lipophilicity, ionophoreti c activity, and RTA-IT enhancement was observed. The compounds with th e highest polar charge showed low intrinsic toxicity, revealed moderat e ionophoretic activity, and were able to enhance RTA-IT only at high concentrations, whereas more lipophilic compounds (with a C28 tail or a phenyl group) showed significant ionophoretic activity and good enha ncing properties.