Ay. Chen et al., DNA MINOR GROOVE-BINDING LIGANDS - A DIFFERENT CLASS OF MAMMALIAN DNATOPOISOMERASE-I INHIBITORS, Proceedings of the National Academy of Sciences of the United Statesof America, 90(17), 1993, pp. 8131-8135
A number of DNA minor groove-binding ligands (MGBLs) are known to exhi
bit antitumor and antimicrobial activities. We show that DNA topoisome
rase (Topo) I may be a pharmacological target of MGBLs. In the presenc
e of calf thymus Topo I, MGBLs induced limited but highly specific sin
gle-strand DNA breaks. The 3' ends of the broken DNA strands are coval
ently linked to Topo I polypeptides. Protein-linked DNA breaks are rea
dily reversed by a brief heating to 65-degrees-C or the addition of 0.
5 M NaCl. These results suggest that MGBLs, like camptothecin, abort T
opo I reactions by trapping reversible cleavable complexes. The sites
of cleavage induced by MGBLs are distinctly different from those induc
ed by camptothecin. Two of the major cleavage sites have been sequence
d and shown to be highly A+T-rich, suggesting the possible involvement
of a Topo I-drug-DNA ternary complex at the sites of cleavage. Differ
ent MGBLs also exhibit varying efficiency in inducing Topo I-cleavable
complexes, and the order of efficiency is as follows: Hoechst 33342 a
nd 33258 >> distamycin A > berenil > netropsin. The lack of correlatio
n between DNA binding and cleavage efficiency suggests that, in additi
on to binding to the minor grooves of DNA, MGBLs must also interact wi
th Topo I in trapping Topo I-cleavable complexes.