Potentiation of the toxicity of mithramycin by bacterial lipopolysaccharide

The lethality for BALB/c mice of 1,3-bis(2-chloroethyl)-1-nitrosourea, cytosine arabinoside, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, hydroxyurea, mithramycin, a polymyxin-like antibiotic (SQ 21,286), polyadenylic polyuridylic acid, procarbazine, 5-[3,3-bis(2-chloroethyl)-1-triazeno]-imidazole-4-carboxamide (TIC-mustard) or uracil arabinoside administered in combination with Escherichia coli lipopolysaccharide (LPS) was measured. Simultaneously administered mithramycin and LPS or TIC-mustard administered 24 h after LPS synergistically killed mice. Concanavalin A potentiated the lethality of TIC-mustard but not of eight other drugs tested. Pretreatment of mice with LPS or lipid A complexed to concanavalin A rendered mice resistant to the lethal action of LPS alone or combinations of LPS and mithramycin. Mithramycin-treated mice were killed by minute amounts of LPS. Mice sensitized to LPS by mithramycin were used to detect endotoxic activity in biological materials, such as commercially available enzymes, and in a complex of lipid A with concanavalin A.