DNA minor groove binding agents interfere with topoisomerase II mediated lesions induced by epipodophyllotoxin derivative VM-26 and acridine derivative m-AMSA in nuclei from L1210 cells.
This study demonstrated that agents capable of interacting with the minor groove in nuclear DNA interfere with topoisomerase II mediated effects of antitumor drugs such as VM-26 and m-AMSA. Distamycin, Hoechst 33258, and DAPI were used as agents capable of AT-specific binding in the minor groove of DNA while producing no profound long-range distortion of DNA structure. In intact nuclei from L1210 cells, these minor groove binders inhibited the induction of topoisomerase II mediated DNA damage (DNA-protein cross-links and DNA double-strand breaks) by VM-26 and m-AMSA. The inhibitory effects of distamycin reflected prevention of formation of new lesions but not reversal of preexisting damage. The minor groove binders did not differentiate between lesions induced by an intercalator, m-AMSA, or by a DNA-nonbinding drug, VM-26. All three groove binders inhibited DNA breaks more strongly than DNA-protein cross-links. The inhibitory potency correlated with the size of minor groove binders and the size of their DNA-binding sites: distamycin (5 bp) greater than Hoechst 33258 (4 bp) greater than DAPI (3 bp). The results showed that DNA minor groove binders are a new type of modulators of the action of topoisomerase II targeted drugs.
Woynarowski
J M
JM
Grace Cancer Drug Center, Roswell Park Memorial Institute, Buffalo, New York 14263.
Sigmund
R D
RD
Beerman
T A
TA
D000677:Amsacrine / Q000494:pharmacology*; D000818:Animals; D006690:Bisbenzimidazole / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects*; D003852:Deoxyribonucleoproteins / Q000378:metabolism; D004214:Distamycins / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007700:Kinetics; D007939:Leukemia L1210 / Q000378:metabolism*; D051379:Mice; D011034:Podophyllotoxin / Q000031:analogs & derivatives*; D013713:Teniposide / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
D004273:DNA, Neoplasm; D003852:Deoxyribonucleoproteins; D004214:Distamycins; D007211:Indoles; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; C007293:DAPI; D013713:Teniposide; D011034:Podophyllotoxin; D006690:Bisbenzimidazole