DNA unwinding and inhibition of T4 DNA ligase by anthracyclines.
The ability to alter DNA tertiary structure of ten anthracycline derivatives whose antitumor potency is known was studied by an assay that makes use of nicked circular DNA and bacteriophage T4 DNA ligase. This assay allows the detection of tertiary structure alterations caused by DNA binding of both intercalating and non-intercalating drugs. The determination of these events can be obtained at different temperatures in the range of activity of DNA ligase. The results indicate that anthracyclines alter the DNA tertiary structure but this property does not correlate with their cytotoxic or antitumor activities. An additional interesting finding was that several anthracyclines inhibit T4 DNA ligase. The inhibition can be complete and is a cubic function of drug concentration. The inhibition of DNA ligase does not correlate with the ability of anthracyclines to alter the tertiary structure of DNA but is dependent from the presence of an amino group on the sugar ring.
Montecucco
A
A
Istituto di Genetica Biochimica ed Evoluzionistica, CNR, Pavia, Italy.
Pedrali-Noy
G
G
Spadari
S
S
Zanolin
E
E
Ciarrocchi
G
G
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D011088:DNA Ligases / Q000037:antagonists & inhibitors*; D004270:DNA, Circular / Q000187:drug effects*; D004926:Escherichia coli / Q000201:enzymology*; D007700:Kinetics; D009279:Naphthacenes / Q000494:pharmacology; D011118:Polynucleotide Ligases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013604:T-Phages / Q000201:enzymology*
D000903:Antibiotics, Antineoplastic; D004270:DNA, Circular; D009279:Naphthacenes; D011088:DNA Ligases; D011118:Polynucleotide Ligases