Enhanced Toxicity for Mice of Vincristine and Other Chemotherapeutic Agents with Salmonella typhosa Endotoxin and Pseudomonas aeruginosa

Abstract

The toxicity of Salmonella typhosa 0901

Enhanced Toxicity for Mice of Combinations of Bacterial Lipopolysaccharide and Vincristine

“…VNC at a dose of 10 mg/kg produced only a slight decrease in body temperature after 16 h, but the combination of 2 mg of LPS/kg and 1 mg of VNC/kg produced a 6.7 C drop in rectal temperature (Table 1). The serum glutamate pyruvate transaminase (SGPT) activities of mice given 2 mg of LPS/kg were elevated 73% within 1 h and 272% after 4 h but returned to control values by 24 h. The SGPT activities of mice given a lethal dose of LPS (15 mg/kg) rose sooner and remained elevated longer but did not rise higher than the SGPT activities of mice given a nonlethal dose of LPS. The SGPT levels of mice given 1 mg of VNC/kg were elevated 240, 490, and 140% at 1, 4, and 24 h, respectively.…”

“…Moreover, the dose-effect curves for combinations of VNC and LPS were parallel to those for drug alone (23) and LPS alone (24), thereby indicating that no new toxic mechanism is involved and that the enhanced mortality results from mutual potentiation. Also, nonlethal doses of Pseudomonas aeruginosa cells were found to be able to substitute for purified LPS in the LPS-VNC synergy (24).…”

“…It has been established previously, however, that the route of administration of LPS and VNC did not influence overall mortality (13) but that simultaneous injection of LPS with VNC resulted in significantly greater lethality than administration either prior to or after drug (24). Moreover, the dose-effect curves for combinations of VNC and LPS were parallel to those for drug alone (23) and LPS alone (24), thereby indicating that no new toxic mechanism is involved and that the enhanced mortality results from mutual potentiation. Also, nonlethal doses of Pseudomonas aeruginosa cells were found to be able to substitute for purified LPS in the LPS-VNC synergy (24).…”

“…It should be noted that VNC is widely used in the treatment of acute leukemia of childhood, in which the incidence of infection with gram-negative bacteria is very high (6). It is important, therefore, to characterize the synergistic toxicity involving LPS and VNC (23,24). An understanding of this adverse interaction could result in more effective utilization of VNC in cancer chemotherapy.…”

“…The Pseudomonas strains were kindly supplied by P. V. Phibbs (Department of Microbiology, Virginia Commonwealth University). The Pseudomonas cultures were grown overnight at 37 C in a nutrient broth containing 3 g of beef extract (Difco), 10 g of peptone (Difco), and 5 g of NaCl per liter of water (24). The bacterial cells were harvested by centrifugation and suspended in sterile 0.15 M NaCl, and the turbidity at 420 nm was measured.…”