Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression
ReviewCellular resistance to topoisomerase-targeted drugs: from drug uptake to cell death
Introduction
Despite recent development of new anticancer agents with improved clinical activities, resistance to antineoplastic drugs remains the biggest obstacle to curative cancer treatment. Cellular resistance includes natural resistance, which is already present prior to treatment, and acquired resistance which occurs as a result of therapy. In addition, tumors may present a more temporal resistance due to iatrogenic factors, such as inappropriate dosage or concomitant administration of other agents which act as inhibitors of macromolecular synthesis.
Natural and acquired resistance are based on the same molecular mechanisms and, with the possible exception of drug-resistant cell lines obtained by mutagenesis, are always multifactorial in nature. The different mechanisms may be divided into three major categories: (1) pretarget events, including drug uptake, metabolism, and intracellular distribution; (2) drug–target interactions; and (3) post-target events, which for topoisomerase inhibitors include macromolecular synthesis, DNA repair, cell cycle progression and mechanisms involved in the regulation of cell death (Fig. 1).
In the following review, we mostly focus on topoisomerase inhibitors with proven clinical activities. We also wish to stress the incredibly varied and multifactorial aspect of drug resistance with particular emphasis on post-target events, an element of drug resistance which is rarely covered in most reviews on DNA topoisomerases and their inhibitors.
Section snippets
Drug uptake and distribution
Before the drug reaches its intracellular target, it has to be taken up (in the case of most topoisomerase inhibitors, most likely by passive diffusion) and transported to the nucleus. Reduced drug accumulation and/or an altered intracellular drug distribution is a dominant feature of many drug-resistant cell lines. The classical MDR (multidrug resistance) phenotype is associated with increased expression/activity of a 170 kDa transmembrane glycoprotein called Pgp which is a product of the MDR1
Drug–target interactions
It is well established that for most clinically used topoisomerase inhibitors, the critical event is the formation of a ternary DNA–topoisomerase–drug complex (the cleavable complex) and not inhibition of topoisomerase activity as such. It follows, that resistance can occur by any mechanism which tends to reduce the interaction between the three partners. This includes: (1) changes in DNA structure; (2) decreased levels of the wild-type enzyme; (3) alterations in its subcellular localization;
Macromolecular synthesis
Although cleavable complex formation is an essential step in the cytotoxic action of topoisomerase inhibitors, it is not sufficient by itself to kill the cells due to the reversible nature of the cleavable complex once the drug is removed. It has been proposed that it is the collision between the moving replication forks and the drug–stabilized covalent topoisomerase–DNA complexes which results in fork arrest, double-stranded DNA breakage [89] and ultimately, cell death. The actual conversion
Acknowledgments
This work was sponsored by la Ligue Nationale contre le Cancer, the French–Polish Scientific and Technological Cooperation Project of the Ministére des Affaires Etrangéres, France and the Committee for Scientific Research (KBN), Poland (Project 76087), la Fondation de France and the Committee for Scientific Research (KBN), Poland (Grant 4P05 043 10).
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