Lipid association improves the therapeutic index of lomustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea] to suppress 36B-10 tumor growth in rats

The therapeutic efficacy and tumor accumulation of a liposome formulation o f 1-(2-chlororthyl)-3-cyclohexyl-1-nitrosourea (CCNU), an effective agent u sed In the treatment of malignant brain tumors, was examined in an animal t umor model. Pharmacokinetic studies in normal and tumor-bearing rats indica ted that a 2-fold greater plasma exposure was achieved with liposome-Formul ated CCNU compared with the Free drug. In Fisher rats bearing s.c. tumors 3 6B-10, tumor growth was delayed substantially when liposomal CCNU was deliv ered compared with free-drug treatment. In single-dose treatments of 20, 35 , and 50 mg/kg, tumor progression after each dose was reduced similar to2-f old with liposomal compared with free CCNU (four animals In each treatment group). Multiple-dose treatments (given as three weekly doses with eight an imals In each treatment group) with cumulative doses of 80 and 100 mg/kg of Free and liposomal CCNU also resulted in a a-fold reduction in tumor progr ession when compared with Free-drug treatment, When drug levels In tumors r elative to plasma were examined, it was observed that tumor drug concentrat ions did not exceed those found in plasma after administration of free CCNU ; after administration of liposomal CCNU, however, turner concentrations ex ceeded those In plasma by nearly 10-fold, These results suggest that the in creased efficacy of liposome-formulated CCNU may be attributable to enhance d drug accumulation in tumor tissues.