The antitumor agent mitoxantrone binds cooperatively to DNA: evidence for heterogeneity in DNA conformation.
The equilibrium binding of the antitumor compound DHAQ, or mitoxantrone [1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9,10- anthracenedione], to various DNAs has been examined by optical titration and equilibrium dialysis methods. At low r (bound drug/DNA base pair) values, r less than 0.03, DHAQ binds, in a highly cooperative manner, to calf thymus and Micrococcus lysodeikticus DNAs. The binding isotherms for the interaction of DHAQ with Clostridium perfringens DNA and poly(dA-dT).poly(dA-dT) exhibit a small positive slope at low r values, suggestive of cooperative binding. In contrast, the binding of DHAQ to poly(dG-dC).poly(dG-dC) shows no evidence of cooperative binding even at very low r values. At higher r values (r greater than 0.05), the binding of DHAQ to all the DNAs studied is characterized by a neighbor-exclusion process. A model is proposed to account for the two modes of binding exhibited in the cooperative binding isotherms. The main feature of the proposed model is that local sequence and structural heterogeneity of the DNA give rise to sets of binding sites to which DHAQ binds in a highly cooperative manner, while the majority of the DNA sites bind DHAQ via a neighbor-exclusion process. This two-site model reproduces the observed binding isotherms and leads to the conclusion that DHAQ binds in clusters to selected regions of DNA. It is suggested that clustering may play a role in the physiological activity of drugs.
Rosenberg
L S
LS
Carvlin
M J
MJ
Krugh
T R
TR
D000818:Animals; D000880:Anthraquinones; D000970:Antineoplastic Agents; D002417:Cattle; D003016:Clostridium perfringens; D004247:DNA; D004269:DNA, Bacterial; D003956:Dialysis; D008837:Micrococcus; D008942:Mitoxantrone; D009690:Nucleic Acid Conformation; D009994:Osmolar Concentration; D011089:Polydeoxyribonucleotides; D013053:Spectrophotometry; D013329:Structure-Activity Relationship; D013950:Thymus Gland
D000880:Anthraquinones; D000970:Antineoplastic Agents; D004269:DNA, Bacterial; D011089:Polydeoxyribonucleotides; D004247:DNA; D008942:Mitoxantrone