Monensin in lipid emulsion for the potentiation of ricin A chain immunotoxins.
The utilization of carboxylic ionophores such as monensin for immunotoxin potentiation may be hampered by the poor solubility and short in vivo half-life of these highly lipophilic compounds. Therefore, the use of monensin formulated in a lipid/water emulsion was investigated for the in vitro and in vivo potentiation of immunotoxins. Monensin in emulsion or in buffer was equally effective for the in vitro potentiation of the cytotoxicity of both anti-human transferrin receptor and anti-carcinoembryonic antigen immunotoxins against target cells. In mice, buffer and lipid emulsion were compared as vehicles for the i.p. administration of monensin. The half-life of monensin in the peritoneal cavity of BALB/c x DBA/2 F1 (CD2F1) mice was increased 20-fold by inclusion in lipid emulsion (13 min versus 0.75 min). Treatment i.p. with anti-human transferrin receptor immunotoxin or anti-carcinoembryonic antigen immunotoxin and monensin emulsion prolonged the survival of mice with macroscopic i.p. tumor xenografts of H-Meso-1 mesothelioma and LS174T colorectal carcinoma (200-250% increased length of median survival). The in vivo antitumor effect of the cell-specific immunotoxin plus monensin emulsion was superior to immunotoxin alone or to immunotoxin plus monensin in buffer (P less than 0.03; Mann-Whitney U test). This indicates that delivery of monensin in preformed lipid emulsion may produce a reservoir effect of the ionophore in the peritoneal cavity of tumor-bearing mice. Nonspecific control immunotoxin plus monensin emulsion produced no increase in survival. Long-term tumor-free survival (greater than 150 days versus a median survival of 25 days for controls) of mice bearing microscopic LS174T xenografts was obtained by treatment with anti-human transferrin receptor immunotoxin plus monensin emulsion. Administration of either monensin in buffer or monensin in emulsion without immunotoxin had no significant effect on survival. Monensin in this pharmacologically available form significantly improved the in vivo efficacy of both anti-human transferrin receptor immunotoxin and anti-carcinoembryonic antigen immunotoxin when used as regional therapy.
Griffin
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Department of Medicine, University of Massachusetts Medical School, Worcester 01655.
Raso
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D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004357:Drug Synergism; D004655:Emulsions; D006207:Half-Life; D006801:Humans; D000922:Immunotoxins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008654:Mesothelioma / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D008985:Monensin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D012276:Ricin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014316:Tritium
D000911:Antibodies, Monoclonal; D004655:Emulsions; D000922:Immunotoxins; D014316:Tritium; D012276:Ricin; D008985:Monensin