Drug interaction effects on antitumour drugs (X): exacerbation of cisplatin lethality by bacterial lipopolysaccharide in mice

Abstract

To determine whether bacterial endotoxin (lipopolysaccharide, LPS from Escherichia coli) could modulate the lethality of cisplatin (CDDP) in mice, animals were treated with LPS (1 mg/kg, intraperitoneally) 24 hr and 1 hr before administration of cisplatin. A 1.6-fold increase in 8-day cumulative mortality was observed in LPS-treated mice compared to the mortality of those injected with saline before CDDP administration. The duration of previous exposure time to LPS appeared to be an important determinant of the potentiating effect, as many more mice died after 24 hr pretreatment than after 1 hr. Because renal toxicity remains a serious limitation to the effective use of CDDP, we determined whether LPS could also enhance CDDP-induced renal injury. CDDP markedly induces an increase in blood urea nitrogen (BUN) levels in LPS-treated mice. Treatment with LPS did not affect urinary excretion or renal tissue levels of total platinum, or the plasma pharmacokinetics of free and total platinum. Despite the potentiating effect of LPS on CDDP-induced lethality, it appeared that LPS can provide some enhancement of kidney function, because pretreatment of LPS enhanced an increase in BUN values.