Schedule-dependent potentiation of lomustine cytotoxicity by amphotericin B in mice

The sensitivity of leukemia cells of AKR/J mice to subsequent lomustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)] exposure was found to vary with time following the ip administration of a single dose or multiple doses of amphotericin B (AmB) (0.5 mg/mouse/dose). Following 1 dose of AmB, leukemia cell sensitivity to CCNU, as measured by a spleen colony assay, reached a maximum by 24 hours with a tenfold increase in cell killing noted over cell killing with CCNU alone (0.15 mg/mouse). Two pretreatments with AmB separated by 24 hours led to a hundredfold increase in cell killing, whereas 4 pretreatments, each separated by 24 hours, gave more than a thousandfold increase in cytotoxicity by 8 hours, gave more than a thousandfold increase in cytotoxicity by 8 hours. Increasing the AmB dose, given as a single injection 24 hours before CCNU, resulted in increased potentiation of CCNU cytotoxicity, which reached a maximum at 0.5 mg/mouse. The kinetics of cell killing following either CCNU alone or the combination of AmB and CCNU were similar, although the extent of cell killing was greater with the combination. The AmB plasma pharmacokinetics for single doses showed a dose-dependent serum peak level and a half-life of about 24 hours for doses up to 1 mg/mouse. Nonlinearity was noted at the dose level of 2 mg/mouse because of saturation of absorption from the peritoneal cavity. These data are of importance for the optimal sequencing and dosing of these drugs for future clinical trials.