Structural requirements for the formation of anthracycline-DNA adducts

A series of anthracyclines (comprising carminomycins I, II and III, and bar minomycin) were tested for their ability to react with DNA to form site-spe cific adducts using an in vitro transcription assay. The requirement for dr ug activation by formaldehyde was also assessed using a transcription assay and HPLC analysis of GC-containing oligonucleotide duplexes. In the absenc e of formaldehyde, barminomycin was the most reactive compound and carminom ycin I the least reactive. The DNA sequence specificity of all anthracyclin es was similar (the most intense binding sites being 5 ' -GC sequences), al though barminomycin was the most selective for 5 ' -GC, Barminomycin adduct s were the most stable at 37 degreesC (no loss in the 48 h time frame studi ed) while carminomycin II and III lesions were least stable (each with a ha lf-life of similar to4-5 h), These results are discussed collectively in te rms of the requirement and contribution of structural elements of the anthr acyclines for the formation of DNA adducts.