Enhanced Toxicity for Mice of Combinations of Bacterial Endotoxin with Antitumor Drugs

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Abstract
The toxicity of Salmonella typhosa 0901W endotoxin to mice was potentiated by (per kilogram) 1 mg of colchicine, 20 mg of emetine, 100 mg of 6-mercaptopurine, 100 mg of 6-methylmercaptopurine riboside, 75 mg of methotrexate, 2 mg of sparsomycin, or 2.5 mg of vinblastine. No potentiation of endotoxin lethality was evident with simultaneously administered (per kilogram): 200 mg of cytosine arabinoside, 450 mg of dibromomannitol, 100 mg of 5-fluorouracil, 125 mg of 5-fluorouracil deoxyriboside, 8 mg of mitomycin C, 1 mg of nitrogen mustard, or 10 mg of tris(1-aziridinyl)-phosphine sulfide. With the exception of colchicine, all drugs prolonged the duration of sleep after the administration of 80 mg of hexobarbital per kg. Simultaneous injection of endotoxin with 100 mg of 6-mercaptopurine per kg, 75 mg of methotrexate per kg, or 1 mg of vincristine per kg resulted in significantly greater lethality than administration either prior to or after the drug. However when endotoxin was administered prior to 100 mg of 5-fluorouracil per kg, lethality was significantly increased. The route of administration of endotoxin and 5-fluorouracil, 6-mercaptopurine, methotrexate, or vincristine did not influence overall lethality. Pretreatment of mice with multiple doses of Escherichia coli endotoxin resulted in a significant reduction in the lethality of 6-mercaptopurine- or vincristine-endotoxin combinations, but had no influence on 5-fluorouracil- or methotrexate-endotoxin combinations. Endotoxin-pretreated mice were more susceptible to vincristine alone and more resistant to high doses of 5-fluorouracil. The lethality of 6-mercaptopurine was increased by simultaneous administration of gram-negative isolates from feces of human patients with neoplastic disease.