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Biological and Biochemical Properties of the 2-Hydroxyl Metabolites of 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea¹

Division of Medical Oncology, Vincent T. Lombardi Cancer Research Center, Georgetown University School of Medicine, Washington, D. C. 20007

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) have been correlated with their relative in vitro alkylating and carbamoylating activities. Both the 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 i.p. L1210 leukemia. However, 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 was CCNU in normal mice. In comparing the antitumor activity produced by a maximum nonlethal dose for each compound, we found that the trans isomer had activity identical to that of CCNU (413 and 410% increased life span compared to control), and the cis isomer had considerably less (152%). Like chiorozotocin, both isomers possess low carbamoylating activity and increased water solubility, two features that have been considered possible contributors to the bone marrow-sparing character of chlorozotocin. However, in the murine model the human bone marrow colony formation (CFU-C) assay neither hydroxylated metabolite of CCNU was associated with reduced myelotoxicity.

¹ Supported in part by Research Grants CH-13 from the American Cancer Society and NIH 1-RO1-CA 17583-O2ET.

² To whom requests for reprints should be addressed.

Received 9/13/77. Accepted 1/ 3/78.