Characterization of DNA damage and cytotoxicity induced in two human colon carcinoma cell lines by cyclodisone

Cyclodisone is an active alkylating antitumor agent that is being considered for Phase 1 clinical trials in humans and is currently undergoing toxicological evaluation. Cyclodisone was found to be more toxic to human colon carcinoma cells of the Mer- phenotype (BE) than cells of the Mer+ phenotype (HT-29). DNA interstrand cross-links were observed in the sensitive cell line but only at concentrations which were extremely toxic. No DNA interstrand cross-links were observed in the resistant cell line. Total DNA cross-links, which reflect both DNA interstrand and DNA-protein cross-linking, were observed in either cell type but were greater in quantity and persisted longer in the sensitive BE cell line, when compared to those produced in the resistant HT-29 cell line. DNA strand breaks were also observed in both cell types and were found to be protein associated. The mechanism of action of cyclodisone would appear to be related to the presence of total DNA cross-links and might involve an, as yet, unidentified DNA-protein interaction.