Lung tumor induction in A/J mice and clastogenic effects in CD-1 mice of the sequence-selective DNA alkylating agents (+)-cc-1065 and (−)-cc-1065

The in vivo genotoxic effects of the antitumor antibiotic, (−)‐CC‐1065, and its unnatural enantiomer, (−)‐CC‐1065, were investigated in two mouse models. These two compounds alkylate AT‐rich regions of double stranded DNA with distinct sequence selectivities. (+)‐CC‐1065 dose‐dependently increased the chromosomal aberration frequency in bone marrow cells of CD‐1 mice from 1.2 ± 0.8% in vehicle control animals to 5.0 ± 1.2%, 11.4 ± 3.9%, and 20.6 ± 2.3% 24 hours following single intravenous doses of 2, 4, and 8 μg/kg, respectively. (−)CC‐1065 was significantly less potent with a maximal response at 8 μg/kg approximately one‐third of that observed for (+)‐CC‐1065. (+)‐CC‐1065 induced a significant (P ± 0.05), three‐fold increase in the number of lung tumors/mouse in strain A/J mice from 0.27 ± 0.15 for vehicle control animals to 0.83 ± 0.15 24 weeks following a single intravenous dose of 8 μs/kg. This effect was paralleled by corresponding threefold increases in the percentage of mice with tumors and the percentage of mice with multiple tumors, compared to vehicle controls. (−)‐CC‐1065 at 8 μg/kg induced 0.67 ± 0.15 tumors/mouse and resulted in slightly smaller increases in the tumor incidence and multiple tumor incidence, compared to (+)‐CC‐1065. The above results demonstrate that single intravenous doses of (+)‐CC‐1065 and (−)‐CC‐1065 which cause chromosomal damage in CD‐1 mice also induce an increased incidence of lung tumors in A/J mice. (+)‐CC‐1065 may have a slightly greater genotoxic potential in vivo than its unnatural enantiomer. This may be attributable to differences in the DNA binding sequence selectivities of the two compounds. Furthermore, when compared on a μ‐moles/kg basis, (+)‐CC‐1065 is > 7,000 × more potent than N‐ethyl‐N‐nitrosourea at inducing a similar tumorigenic response in the A/J mouse lung tumor bioassay. © 1995 Wiley‐Liss, Inc.