Comparison of the properties of metabolites of CCNU.

Properties of the six isomeric N-(2-chloroethyl-N′-(hydroxycyclohexyl-N-nitrosoureas, which have been identified by other investigators as metabolites of N-(2-chloroethyl-N′-cyclohexyl-N-nitrosourea (CCNU), have been compared with those of CCNU and 2-(2-chloroethyl)nitrosoamino]-carbonyl]amino]-2-deoxy-D-glucose (chlorozotocin). There are significant differences in the physicochemical, chemical, and biological properties of these metabolites, and the properties of some of them are significantly different from those of CCNU and chlorozotocin. The position of the hydroxy group and the steric configuration of the compound markedly affect the alkylating and carbamoylating activities of the compounds. The metabolites having the higher alkylating activities and the lower carbamoylating activities produce lethal toxicity to mice at lower molar doses but have somewhat better therapeutic indexes. The data are consistent with the hypothesis that the biological effects observed following the administration of CCNU are due to a large extent to the major metabolites with lesser effects contributed by the minor metabolites. Some of the metabolites have slightly better therapeutic indexes against murine leukemia L1210 than CCNU and chlorozotocin, and they are more soluble in water than CCNU but are active against both intraperitoneally implanted and intracerebrally implanted L1210 leukemia. There might be some therapeutic advantage to administering one of the minor metabolites instead of CCNU or chlorozotocin to cancer-bearing animals.