monensin and Mesothelioma

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.

Topics: Animals; Antibodies, Monoclonal; Body Weight; Cell Line; Cell Survival; Colorectal Neoplasms; Drug Synergism; Emulsions; Half-Life; Humans; Immunotoxins; Mesothelioma; Mice; Mice, Nude; Monensin; Ricin; Transplantation, Heterologous; Tritium

Immunotoxins directed against human transferrin receptor have been evaluated in a nude mouse model of human malignant mesothelioma. Immunotoxins were constructed by linking ricin A chain to murine monoclonal antibodies reactive with the human transferrin receptor. A chain was obtained either by isolation from the parent toxin or by recombinant DNA techniques. These immunotoxins acted as potent in vitro cytotoxins against human malignant mesothelioma cells (H-MESO-1) (ID50, 2 X 10(-9) M). Cytotoxic potency and kinetics of cell kill were potentiated in vitro by the carboxylic ionophore monensin. For in vivo trials, nude mice were injected i.p. with 6-9 X 10(6) human malignant mesothelioma cells 24 h prior to the start of i.p. immunotoxin treatments. The survival of tumor-bearing mice was extended by 149-404%, representing a probable cell kill of 2-4 logs. Specificity of this antitransferrin receptor immunotoxin response was confirmed by the ineffectiveness of irrelevant control immunotoxins and blockade of specific immunotoxin action by excess free antibody. Monensin showed limited in vivo potentiation of immunotoxin effect, but a derivative formed by esterification of monensin with linoleic acid gave improved survival times over treatment with immunotoxin alone. Immunotoxins constructed with ricin A chain have significant tumoricidal activity in this model of regional antitumor therapy. These results may have direct relevance for treatment of i.p. malignancy in clinical settings.

Topics: Animals; Antineoplastic Agents; Cell Survival; Cytotoxicity, Immunologic; Disease Models, Animal; Humans; Immunotoxins; Injections, Intraperitoneal; Mesothelioma; Mice; Mice, Inbred BALB C; Mice, Nude; Monensin; Neoplasm Transplantation; Receptors, Transferrin; Ricin; Transplantation, Heterologous