Molecular pharmacology of the anthracycline drug 9,10-anthracenedicarboxaldehyde bis[(4,5-dihydro-1 H-imidazol-2-yl)hydrazone] dihydrochloride (Cl 216,942).

9,10-Anthracenedicarboxyaldehyde bis[(4,5-dihydro-1H-imidazol-2yl)hydrazone] dihydrochloride (Cl 216,942) is a new anthracene bishydrazone derivative which has shown antitumor activity in Phase I trials against both hematological cancers and solid tumors. The effects of Cl 216,942 on L1210 mouse leukemia cells were studied with the nucleoid sedimentation and alkaline elution assays. Evidence for Cl 216,942 intercalation into cellular DNA was obtained in exponentially growing cells by comparing the L1210 nucleoid sedimentation behavior in neutral sucrose gradients of ethidium bromide with nucleoids from Cl 216,942-treated cells. A 1-hr treatment of exponentially growing L1210 cells with Cl 216,942 induced both protein-associated DNA single-strand breaks and DNA-protein crosslinks as detected by the alkaline elution assay. The DNA strand break and DNA-protein cross-link frequencies were found to be within a factor of 2 of each other over a range of Cl 216,942 concentrations. The dose response for the induction of DNA damage showed a linear decrease up to 10 micrograms/ml, but this was followed by a decrease in damage at dose levels greater than 10 micrograms/ml. The biphasic dose response could not be explained by changes in the cellular uptake of Cl 216,942. The kinetics of Cl 216,942 induction of DNA damage after a 1-hr treatment showed that at the dose which gave maximum damage the degree of damage (10 micrograms/ml) decreased with further incubation, but at a higher dose (20 micrograms/ml) DNA damage increased with postincubation at 37 degrees. The cytotoxicity produced by Cl 216,942 at a given frequency of protein-associated strand breaks was low. Cl 216,942 thus appeared to belong to a low-toxicity group of DNA intercalators.