Monensin is a carboxylic ionophore which dissipates proton gradients across cell membranes. Monensin is known to potentiate the cytotoxic activity of immunotoxins (antibody-toxin conjugates) directed against several human tumor-associated antigens. We have investigated the effect of monensin on an immunotoxin cytotoxic to the human breast cancer cell line MCF-7. This immunotoxin is composed of an antibody directed against a human breast cancer membrane antigen, and ricin A chain, which has been produced by recombinant DNA techniques. In a 16-hour cytotoxicity assay, monensin reduced 34-fold the median inhibitory dose, from 1.4 × 10-8M (without monensin) to 4.1 × 10-10M (with monensin). In timed cytotoxicity assays, 50% of control protein synthesis was reached in immunotoxin treated cells 8-fold faster in the presence of monensin (0.5 hours) than in its absence (4 hours). Monensin produced no enhancement of immunotoxin effect on a control cell line, nor on a control immunotoxin on MCF-7 cells, demonstrating specificity of monensin effect. In addition, specific immunotoxin alone or with monensin produced no toxicity on MCF-7 cells maintained at 23°C. These results suggest that both binding and internalization of immunotoxin are necessary for the monensin effect. Monensin was a potent enhancer of immunotoxin effect on human breast cancer cells. This effect occurs without the presence of ricin B chain in the conjugate.
Received December 22, 1986; accepted May 15, 1987.
Address correspondence and reprint requests to Dr. T. W. Griffin at Department of Medicine (Oncology), University of Massachusetts Medical Center, 55 Lake Avenue North, Worcester, MA 01605, U.S.A.
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