DNA Topoisomerases and Cancer (Cancer Drug Discovery and Development)

Recent work has shown that there may be contexts where the level of Top2 protein predicts clinical activity as well as many contexts where it does not. With the understanding of mechanisms of drug action and improved patient survival rates has come the appreciation that clinical treatment with drugs targeting Top2 can lead to the dire consequence of secondary malignancies. An important goal of present and future work is to maximize therapeutic efficacy of therapy using Top2 targeting agents while minimizing the risks of secondary malignancy and other toxicities.

This review highlights recent work that is relevant to maximizing the potential of Top2 as an anti-cancer drug target. Drugs targeting Top2 are divided into two broad classes. The first class, which includes most of the clinically active agents including etoposide, doxorubicin, and mitoxantrone, lead to increases in the levels of Top2: A second class of compounds inhibits Top2 catalytic activity, but do not generate increases in the levels of Top2 covalent complexes. This second class of agents is thought to kill cells through elimination of the essential enzymatic activity of Top2 and is therefore termed catalytic inhibitors Fig.

Top2 can be inhibited at several different points in the enzyme reaction cycle, which can generate different biochemical and cellular consequences.

Targeting DNA topoisomerase II in cancer chemotherapy

One simple mode of inhibition is to inhibit a step early in the enzyme reaction cycle. For example, competitive inhibitors of ATP binding prevent strand passage, and do not generate enzyme mediated DNA damage. While agents such as novobiocin and coumermycin not shown on the figure inhibit both prokaryotic and eukaryotic Top2s, they are either less potent as well as relatively nonspecific e.

Similar effects would occur with inhibitors that prevent the binding of Top2 to DNA such as aclarubicin. Agents that prevent DNA cleavage by Top2, such as merbarone would also be expected to act as simple catalytic inhibitors. While merbarone clearly prevents DNA cleavage by Top2 , merbarone clearly affects other targets besides Top2.

Topoisomerases as anticancer targets.

This mode of inhibition occurs for most currently used Top2 targeting agents including anthracyclines and epipodophyllotoxins, as well as for agents that target prokaryotic type II topoisomerases. These agents prevent enzyme turnover, and therefore greatly inhibit the enzyme catalytic activity, however, the clearest effect is the generation of high levels of Top2: Therefore, these inhibitors generate DNA damage, and interfere with many DNA metabolic events such as transcription and replication.

Since agents of this class convert Top2 into an agent that induces cellular damage, they have been termed topoisomerase poisons. Top2 can be inhibited after strand passage is completed, but prior to ATP hydrolysis and dissociation of N-terminal dimerization. As is the case with Top2 poisons, bisdioxopiperazines inhibit Top2 catalytic activity mainly by blocking enzyme turnover.

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Although these agents are frequently termed catalytic inhibitors, they leave Top2 trapped on DNA, and may interfere with DNA metabolism in ways distinct from the inhibitors described in pathway A. Nonetheless, since bisdioxopiperazines are relatively specific for Top2, they are the most commonly used catalytic inhibitors of Top2 in mammalian cells There are several lines of evidence indicating the importance of the distinction between Top2 poisons and Top2 catalytic inhibitors.

DNA Topoisomerases and Cancer : Yves Pommier :

Studies in yeast and mammalian cells demonstrated that resistance to Top2 poisons is recessive, i. The importance of enzyme mediated DNA damage is also demonstrated by observations that Top2 poisons rapidly elicit DNA damage responses such as ATM phosphorylation and activation of downstream damage responses 7 — 9. Resistance to Top2 targeting drugs in mammalian cells is frequently associated with reduced expression of Top2 isoforms 6 , suggesting that resistance is mediated through a reduction in enzyme mediated DNA damage, rather than through enhancing available enzyme activity where resistance would arise from increased expression of Top2 isoforms.

The generation of high levels of Top2 DNA covalent complexes has profound effects on cell physiology. Top2 poisons effectively block transcription and replication. DNA strand breaks are rapidly detected following treatment with Top2 poisons, and most of the strand breaks are protein linked, as expected 10 , Cells subsequently commit to apoptosis, in fact etoposide is a very commonly used agent to study apoptotic processes The pattern of responses observed with catalytic inhibitors of Top2 differ from that observed with Top2 poisons, albeit with several important complications.

Most catalytic inhibitors of Top2 are not specific for Top2 inhibition see Box 1 with the exception of bisdioxopiperazines. While bisdioxopiperazines generate DNA damage responses following long exposure 13 , they do not produce a DNA damage response following short term exposure 14 — Importantly, in cell culture experiments, catalytic inhibitors of Top2 antagonize the toxicity of Top2 poisons 18 , indicating that the agents act by separable mechanisms.

An important and still unanswered question is whether Top2 inhibitors that are not poisons might be active anti-cancer agents. This issue is addressed in the concluding sections of this review.

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Drugs targeting topoisomerase II fall into two categories, Top2 poisons and Top2 catalytic inhibitors. Many Top2 poisons have demonstrated anti-cancer activity. Top2 poisons can be further sub-divided into intercalating and non-intercalating poisons. The intercalators are chemically diverse, and include doxorubicin and other anthracyclines, mitoxantrone, mAMSA, and a variety of other compounds that are not currently in clinical use such as amonafide and ellipticine 5.

Other than their ability to intercalate in DNA, there is no obvious chemical similarity that could explain the ability of these compounds to trap Top2. Importantly, some compounds, such as oAMSA and ethidium bromide have little ability to poison Top2, suggesting that intercalation of a small molecule is insufficient to trap Top2 as a covalent complex on DNA 1 , Some of the intercalating Top2 targeting drugs, notably the anthracyclines, produce a variety of effects on cells, including many effects that are independent of their action against Top2.

For example, doxorubicin is known to produce free radicals, to cause membrane damage, and to induce protein: Whether Top2 is the most important target of anthracyclines remains a controversial issue, reviewed in , although some of the results presented in the text support the hypothesis that Top2 is the most relevant target for both clinical response and cardiotoxicity. For alternate hypotheses, see — Several classes of compounds have been described that inhibit Top2 activity but do not increase DNA cleavage.

Most prominent are the bisdioxopiperazines, which inhibit the enzyme ATPase activity non-competitively and trap Top2 as a closed clamp 74 , , ICRF, a bisdioxopiperazine, is used as a cardioprotectant in some patients treated with anthracyclines. Other Top2 catalytic inhibitors include novobiocin — , merbarone , and the anthracycline aclarubicin All three compounds have significant targets besides Top2 , , ; therefore these compounds have not been useful in assessing the feasibility of using catalytic inhibitors of Top2 as an anti-cancer therapy.

Merbarone has attracted interest because it is the only agent that has been found to inhibit Top2 cleavage of DNA but not affect protein: This compound may be particularly useful in assessing the effects of catalytic inhibition of Top2. Several other catalytic inhibitors have been described, however, their detailed mechanism of action has not been explored.

Is there a need for new and different Top2 drugs? The first answer to this question is a resounding yes, since Top2 targeting is clearly successful in a wide variety of contexts. It is clear from broiad clinical experience that Top2 targeting drugs can be safely and effectively combined with many other agents. The Top2 targeting drugs in clinical use were identified not based on their activity against Top2, but mainly on empirical anti-tumor activity. Therefore, it would be expected that rational screening would lead to potent and specific Top2 poisons.

It would be very desirable to know if greater potency and specificity would enhance clinical response. An important question is whether isotype specific Top2 poisons can be identified, since the two enzymes share catalytic mechanisms, and a great deal of amino acid homology in their catalytic domains.

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The search for improved Top2 targeting drugs will require further advances in both the biochemistry and structural biology of drug action. While the structures that have already been determined have provided important insights into the biochemistry of Top2, the only structure of Top2 bound to a drug that has been determined is the ATPase domain of Top2 bound to ICRF The grail for understanding the biochemistry of a drug like etoposide is the determination of a ternary complex between drug, protein, and DNA.

Home Contact Us Help Free delivery worldwide. Description DNA topoisomerases represent an essential family of DNA processing enzymes and a large number of topoisomerase inhibitors are used clinically for the treatment of various human cancers.

Novels drugs are in clinical development both against type I and type II topoisomerases. The book will include basic biochemical and structural reviews for the cancer-relevant topoisomerases. It will describe how topoisomerase dysfunctions can damage the genome and increase the risk of cancers, and the involvement of topoisomerases in programmed cell death. The book will also present the various topoisomerase inhibitors in clinical use and development and their molecular and cellular mechanisms of action.

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