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Kinetic and Equilibrium Studies of the Interaction of Amsacrine and Anilino Ring-substituted Analogues with DNA¹

Cancer Research Laboratory, School of Medicine, University of Auckland, Private Bag, Auckland, New Zealand [W. A. D.], and Experimental Chemotherapy Unit, Cancer Institute, 481 Little Lonsdale Street, Melbourne, Victoria 3000, Australia [L. P. G. W.]

The kinetic stability of complexes of the clinical antileukemic drug amsacrine and anilino ring-substituted analogues with DNA has been studied by using the surfactant sequestration technique in a stopped-flow spectrophotometer. In addition, viscometric measurements using covalently closed circular DNA and displacement measurements of DNA-bound ethidium have been performed to evaluate helix unwinding angles and association constants, respectively. Amsacrine and its analogues dissociate from DNA by a complex kinetic pathway which involves at least three discernible transiently bound forms of the drug. Dissociation time constants for amsacrine are found to range from <1 to 6 ms in buffer of ionic strength 0.1, and the biomolecular association rate constant is >10⁶ M^-1 s^-1. We find that amsacrine forms one of the weakest intercalation complexes among the compounds studied, as judged by the criteria of kinetic stability, affinity, and chromophore-base pair stacking interactions. Unlike other compounds of this broad class (intercalating chromophores bearing sterically-demanding side chains), addition of the bulky side chain has little effect on the kinetic stability of the drug-DNA complexes, suggesting that the acridinesulfonanilides may intercalate into DNA from the less sterically demanding major groove of the helix. Such a binding geometry would facilitate the formation of the previously proposed ternary complex between amsacrine, DNA, and gene-regulatory enzymes (e.g., topoisomerases and repressors) which are known to bind in the major groove.

¹ This work was supported by grants from the Auckland Division of the Cancer Society of New Zealand, the Medical Research Council of New Zealand, and the Australian Research Grants Scheme.

² To whom requests for reprints should be addressed.

Received 4/15/85. Revised 9/26/85. Revised 12/ 9/85. Accepted 12/26/85.