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.
Cutts
S M
SM
Department of Biochemistry, La Trobe University, Bundoora, Victoria, Australia.
Parker
B S
BS
Swift
L P
LP
Kimura
K I
KI
Phillips
D R
DR
D018943:Anthracyclines / Q000737:chemistry / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000494:pharmacology*; D001483:Base Sequence; D002360:Carubicin / Q000737:chemistry / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003432:Cross-Linking Reagents; D018736:DNA Adducts / Q000737:chemistry* / Q000187:drug effects; D004273:DNA, Neoplasm / Q000737:chemistry / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D005557:Formaldehyde / Q000737:chemistry; D006801:Humans; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D004273:DNA, Neoplasm; C054281:barminomycin I; D005557:Formaldehyde; D004317:Doxorubicin; D002360:Carubicin