Biological activity and molecular interaction of a netropsin-acridine hybrid ligand with chromatin and topoisomerase II.
A hybrid molecule, which combines an anilinoacridine chromophore related to the antitumour drug amsacrine (m-AMSA) and a bispyrrole moiety analogous to the antiviral agent netropsin, has been examined for its ability to bind chromatin and to modulate the activity of topoisomerase II. The results show that the presence of histones does not alter the bimodal DNA binding process. Intercalation of the acridine and groove binding of the netropsin part of the drug are both observed with chromatin preparations. Moreover, the hybrid has a clear topoisomerase II-DNA cleavable complex-inducing activity close to that of m-AMSA. The role of the two parts of the hybrid ligand is discussed in relation to ternary complex formation. Two cell lines (L1210 leukemia and MCF7 mammary carcinoma) were compared in their sensitivity to the tested ligand. The drug, which appears to be an efficient growth inhibitor of leukemic cells in vitro, reveals moderate activity against P388 leukemia in vivo. The biological activity of the hybrid may derive from a mechanism that involves DNA binding and topoisomerase II inhibition. This study demonstrates that agents which intercalate and bind to the minor groove of DNA simultaneously represent a new class of drugs interfering with topoisomerase II and provide opportunities for the development of new antitumour agents.
Bailly
C
C
INSERM Unité 16, Lille, France.
Collyn-d'Hooghe
M
M
Lantoine
D
D
Fournier
C
C
Hecquet
B
B
Fosse
P
P
Saucier
J M
JM
Colson
P
P
Houssier
C
C
Hénichart
J P
JP
D000677:Amsacrine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism*; D004249:DNA Damage; D015195:Drug Design; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D009429:Netropsin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology
D002843:Chromatin; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D009429:Netropsin; D005472:Fluorouracil