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Chapter 4 : Quinolones and Eukaryotic Topoisomerases

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Abstract:

This chapter reviews the literature with respect to the reported effects of quinolones on topoisomerase II in vitro and considers those reports relevant to the effects of quinolones on whole cells. The initial part of the chapter describes in more detail some of the enzymatic properties of topoisomerase II and the consequences to the cell of the actions of drugs that are known to target this important enzyme. Topoisomerase II alters the topological state of nucleic acids by passing an intact helix of DNA through a transient break that it generates in a separate helix. As a consequence of its double-stranded DNA passage reaction, the enzyme can relax from supercoiled DNA as well as knot-unknot or catenate-decatenate double stranded nucleic acids. A limited number of studies that evaluate the interactions of quinolones with eukaryotic topoisomerase I are available. Quinolones have been shown to be less inhibitory for topoisomerase I than for DNA gyrase. In one study, nalidixic acid and ofloxacin at concentrations of up to 1,000 μg/ml showed no inhibitory activity against calf thymus nuclear topoisomerase I relaxation activity. Evidence that quinolones and antitumor inhibitors of topoisomerase II show both a common inhibitor-binding site and a common mechanism of action (i.e., increase in levels of enzyme-DNA cleavage complexes) comes from studies using mutants of the T4 phage enzyme. Quinolones such as CP-67,015, CP-115,953, A-65281, A-65282, and WIN 58161 are clearly different from quinolones developed so far for clinical use with respect to their potency against topoisomerase II.

Citation: Gootz T, Osheroff N. 2003. Quinolones and Eukaryotic Topoisomerases, p 69-89. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch4
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Figure 1

The six steps in the catalytic cycle of topoisomerase II. (i) The homodimer binds to DNA at points of helix-helix juxtaposition; (ii) in the presence of magnesium, topoisomerase II transiently cuts and religates the cleavage helix; (hi) on binding of two ATP molecules the enzyme-DNA complex undergoes a structural reorientation; (iv) following DNA strand passage topoisomerase II reestablishes a DNA cleavage-religation equilibrium; (v) topoisomerase II hydrolyzes the second bound ATP to ADP and P; (vi) the enzyme is recycled following hydrolysis of ATP.

Citation: Gootz T, Osheroff N. 2003. Quinolones and Eukaryotic Topoisomerases, p 69-89. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch4
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Image of Figure 2
Figure 2

Structures of novel fluoroquinolones that act against topoisomerase II.

Citation: Gootz T, Osheroff N. 2003. Quinolones and Eukaryotic Topoisomerases, p 69-89. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch4
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Figure 3

Effects of CP-115,953 on the DNA cleavage (A) and religation (B) reactions of topoisomerase II. (A) Comparative cleavage titration of CP-115,953 and etoposide tested at the concentrations shown on the top of the gel photograph. CP-115,953 is more potent at enhancing topoisomerase II-mediated DNA cleavage product (form III DNA) from supercoiled DNA (form I) than is etoposide at comparable concentrations. (B) Religation of cleavage product was initiated by shifting assay mixtures from 30 to 55°C. Results obtained with 50 µM CP-115,953 are compared with those obtained in the absence of drug or in the presence of 100 µM etoposide. The drug concentrations used generated similar levels of enzyme-mediated DNA breakage. Data are plotted in a semilogarithmic fashion as the loss of linear DNA versus time. The percent linear DNA for each assay was set arbitrarily to 100% at time zero. Plots represent the averages of three independent experiments (average standard error, ≤5% ). Panel B is reproduced from reference 148 with permission.

Citation: Gootz T, Osheroff N. 2003. Quinolones and Eukaryotic Topoisomerases, p 69-89. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch4
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Tables

Generic image for table
Table 1

Relative DNA gyrase selectivities of some quinolones

Citation: Gootz T, Osheroff N. 2003. Quinolones and Eukaryotic Topoisomerases, p 69-89. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch4
Generic image for table
Table 2

Influence of stereochemistry on the inhibitory activities of ofloxacin derivatives for DNA gyrase and topoisomerase IIª

Citation: Gootz T, Osheroff N. 2003. Quinolones and Eukaryotic Topoisomerases, p 69-89. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch4

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