Printed in U.S.A. 1-(2CHLOROETHYL)-3-CYCLOHEXYL- I-NITROSOUREA (CCNU) MODULATES RAT LIVER MICROSOMAL CYCLOPHOSPHAMIDE AND IFOSPHAMIDE ACTIVATION BY

The alkylating anticancer drug 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU; lomustine) is frequently administered to cancer patients as part of a combination chemotherapy regimen. Previous studies have indicated that CCNU treatment of adult male rats leads to prolonged decreases In liver cytochrome P450 (CYP)-mediated enzyme activities. Because the alkylating agent prodrugs cyclophos-phamide and Ifosphamide are known to be activated by liver cyto-chrome P450 enzymes, the potential for interaction between CCNU and these oxazaphosphonnes was examined. Treatment of adult male rats with a single dose of CCNU (30 mg/kg ip) resulted in a progressive loss of liver microsomal cyclophosphamide and ifos-phamide hydroxylation activities In vitro (30-60 % decrease after 7-27 days). The individual liver P450 forms modulated by CCNU were then identified using P450 form-specific microsomal testosterone hydroxylase assays. CCNU treatment was found to decrease sub