RELATIONSHIP BETWEEN CYTOTOXICITY AND DNA STRAND BREAKAGE PRODUCED BY ADRIAMYCIN AND OTHER INTERCALATING AGENTS

Intercalating agents were compared with respect to cytotoxicity and DNA damage in order to further clarify the mechanism of action of this important group of anti-tumor drugs. Using the DNA alkaline elution technique, we have previously reported that when L1210 cells are exposed to a variety of intercalators, DNA single strand breaks are formed. The single strand breaks are spatially associated with DNA-protein crosslinks and the breaks and cross-links occur with approximately equal frequency. In this work, the cytotoxic potency of these drugs were compared using a soft agar colony forming assay. Ellipticine, which had produced the greatest frequency of single strand breaks, was only weakly toxic while adriamycin and actinomycin D exhibited potent cytotoxicity but produced fewer single strand breaks per unit drug concentration. To test the possibility that DNA repair processes may be involved in the cytotoxicity of intercalating agents, drug-treated cells were allowed to form colonies in the presence of caffeine, an inhibitor of DNA replication repair. Cytotoxicity of ellipticine, actinomycin D and hycanthone were significantly increased while that of adriamycin was diminished. We conclude that intercalating agents cause the formation of protein-associated DNA breaks but the role of these breaks in drug-induced cytotoxicity is unclear. Response to post-treatment incubation with caffeine suggests that the mechanism of cytotoxicity with adriamycin may differ in important respects from that of other intercalating agents. Extensions of these studies may be useful in elucidating the molecular basis for the biological interaction between radiation and intercalators. © 1979.