BIOLOGICAL AND BIOCHEMICAL PROPERTIES OF 2-HYDROXYL METABOLITES OF 1-2-CHLOROETHYL)-3-CYCLOHEXYL-1-NITROSOUREA

  • 1 January 1978
    • journal article
    • research article
    • Vol. 38  (4) , 1070-1074
Abstract
The lethal and bone marrow toxicity and antitumor activity of the cis- and trans-2-hydroxylated metabolites of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) were correlated with their relative in vitro alkylating and carbamoylating activities. Both isomers have considerably greater alkylating activity and shorter chemical half-lives than the parent compound and on a molar basis have greater antitumor activity against intraperitoneal L1210 leukemia. In terms of molar doses resulting in the death of 10% of normal mice, the cis- and trans-2 isomers were 2- and 3-fold more toxic than CCNU in normal mice. In comparing the antitumor activity produced by a maximum nonlethal dose for each compound, trans isomer had activity identical to that of CCNU (413 and 410% increased life span compared to control), and the cis isomer had less (152%). Like chlorozotocin, both isomers possess low, carbamoylating activity and increased water solubility, 2 features considered possible contributors to the bone marrow-sparing character of chlorozotocin. In the murine model and human bone marrow colony formation (CFU-C) assay neither hydroxylated metabolite of CCNU was associated with reduced myelotoxicity.