Structural requirements for the formation of anthracycline-DNA adducts.

A series of anthracyclines (comprising carminomycins I, II and III, and barminomycin) were tested for their ability to react with DNA to form site-specific adducts using an in vitro transcription assay. The requirement for drug activation by formaldehyde was also assessed using a transcription assay and HPLC analysis of GC-containing oligonucleotide duplexes. In the absence of formaldehyde, barminomycin was the most reactive compound and carminomycin I the least reactive. The DNA sequence specificity of all anthracyclines was similar (the most intense binding sites being 5'-GC sequences), although barminomycin was the most selective for 5'-GC. Barminomycin adducts were the most stable at 37 degrees C (no loss in the 48 h time frame studied) while carminomycin II and III lesions were least stable (each with a half-life of approximately 4-5 h). These results are discussed collectively in terms of the requirement and contribution of structural elements of the anthracyclines for the formation of DNA adducts.