Sequence-selective topoisomerase II inhibition by anthracycline derivatives in SV40 DNA: relationship with DNA binding affinity and cytotoxicity.
Topoisomerase II mediated double-strand breaks produced by anthracycline analogues were studied in SV40 DNA. The compounds included doxorubicin, daunorubicin, two doxorubicin stereoisomers (4'-epimer and beta-anomer), and five chromophore-modified derivatives, with a wide range of cytotoxic activity and DNA binding affinity. Cleavage of 32P-end-labeled DNA fragments was visualized by autoradiography of agarose and polyacrylamide gels. Structure-activity relationships indicated that alterations in the chromophore structure greatly affected drug action on topoisomerase II. In particular, removal of substituents on position 4 of the D ring resulted in more active inducers of cleavage with lower DNA binding affinity. The stereochemistry between the sugar and the chromophore was also essential for activity. All the active anthracyclines induced a single region of prominent cleavage in the entire SV40 DNA, which resulted from a cluster of sites between nucleotides 4237 and 4294. DNA cleavage intensity patterns exhibited differences among analogues and were also dependent upon drug concentration. Intensity at a given site depended on both stimulatory and suppressive effects depending upon drug concentration and DNA sequence. A good correlation was found between cytotoxicity and intensity of topoisomerase II mediated DNA breakage.
Capranico
G
G
Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20892.
Zunino
F
F
Kohn
K W
KW
Pommier
Y
Y
D000677:Amsacrine / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001483:Base Sequence; D004279:DNA, Viral / Q000187:drug effects* / Q000378:metabolism; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008969:Molecular Sequence Data; D015394:Molecular Structure; D013539:Simian virus 40 / Q000235:genetics*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013713:Teniposide / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
D000903:Antibiotics, Antineoplastic; D004279:DNA, Viral; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D004317:Doxorubicin; D013713:Teniposide; D003630:Daunorubicin