Enhanced toxicity for mice of vincristine and other chemotherapeutic agents with Salmonella typhosa endotoxin and Pseudomonas aeruginosa

Abstract

The toxicity of Salmonella typhosa 0901 W endotoxin for BALB/c mice was potentiated by the administration of 375 mg of cyclophosphamide per kg, 16 mg of daunomycin per kg, 80 mg of methotrexate per kg, 8 mg of pactamycin per kg, 20 mg of polyinosinic-polycytidylic acid per kg, 1,000 mg of procarbazine per kg, and 1 or 4 mg of vincristine per kg. l-Asparaginase (20,000 units per kg) failed to potentiate endotoxin. Sedation following administration of 45 mg of pentobarbital per kg was prolonged in mice that had received 20,000 units of l-asparaginase per kg, 4 mg of daunomycin per kg, 120 mg of methotrexate per kg, 8 mg of pactamycin per kg, 10 mg of polyinosinic-polycytidylic acid per kg, 500 mg of procarbazine per kg, 2 mg of vincristine per kg, 2 mg of endotoxin per kg, or multiple doses of endotoxin. Mice pretreated with multiple endotoxin doses experienced a significant reduction in their lethal responses due to vincristine-endotoxin combinations; however, endotoxin-pretreated mice were more susceptible to vincristine alone than were normal mice. Simultaneous administration of 1 or 2 mg of vincristine per kg and 1 mg of endotoxin per kg produced greater lethality than sequential regimens. Pretreatment of mice with 65 mg of phenobarbital per kg on 4 consecutive days protected against vincristine-endotoxin combinations. Liver homogenates prepared from mice exposed previously to vincristine were capable of inactivating endotoxin. Vincristine lethality was increased by simultaneous administration of heat-killed cells of Pseudomonas aeruginosa isolated from mouse feces.