AUC-Dependent Cytotoxicity of Cyclophosphamide against Human Tumors Transplanted into Nude Mice

We studied the cytotoxicity of cyclophosphamide following the administration of phenobarbital or chloral hydrate to nude mice bearing human tumor xenografts. Cyclophosphamide, 60mg/kg, was injected intraperitoneally once a week for four weeks. The antitumor efficacy of cyclophosphamide was not altered by pretreatment with phenobarbital, but was significantly increased by pretreatment with chloral hydrate. In a parallel study, we measured the concentration of blood NBP-alkylating metabolites in nude mice after administration of cyclophosphamide, 60mg/kg. The AUC (area under blood decay curve) values of NBP-alkylating metabolites were 299±39, 270±13, and 521±57nmol eq nor-mustard ml-1·h in the controls, phenobarbital-pretreated, and chloral hydrate-pretreated groups, respectively. In contrast, Cmax (maximal concentration) values did not show any significant differences among these three groups. An increase in the AUC value of NBP-alkylating metabolites might have led to the stimulation of cytotoxicity of cyclophosphamide in the chloral hydrate-pretreated group. These results indicate that cyclophosphamide possesses AUC-dependent cytotoxicity against human tumor.