DNA topoisomerase II rescue by catalytic inhibitors: A new strategy to improve the antitumor selectivity of etoposide

doi:10.1016/S0006-2952(97)00116-0

Biochemical Pharmacology

Volume 54, Issue 7, 1 October 1997, Pages 755-759

https://doi.org/10.1016/S0006-2952(97)00116-0 Get rights and content

Abstract

The nuclear enzyme DNA topoisomerase II (topo II) is the target of important antitumor agents such as etoposide. Recent work has classified topo II targeting drugs into either topo II poisons that act by stabilizing enzyme-DNA cleavable complexes leading to DNA breaks, or topo II catalytic inhibitors that act at stages in the catalytic cycle of the enzyme where both DNA strands are intact and, therefore, do not cause DNA breaks. Accordingly, catalytic inhibitors are known to abrogate DNA damage and cytotoxicity caused by topo II poisons. In this commentary, we have focused on the possibilities of enabling high-dose therapy with the topo II poison etoposide by protection of normal tissue with catalytic inhibitors, analogous to folinic acid rescue in high-dose methotrexate treatment. Thus, we have demonstrated recently that ( + )-1,2-bis(3,5-dioxopiperazinyl-1-yl) propane (ICRF-187) enabled a 3- to 4-fold dose escalation of etoposide in mice. Two high-dose etoposide models are described, namely use of the weak base chloroquine in tumors with acidic extracellular pH and targeting of CNS tumors with protection of normal tissue by the bisdioxopiperazine ICRF-187. In conclusion, high supralethal doses of topo II poisons in combination with catalytic inhibitor protection form a new strategy to improve the antitumor selectivity of etoposide and other topo II poisons. Such an approach may be used to overcome problems with drug resistance and drug penetration.

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Systemic chemotherapy is an applicable treatment option [4]. The DNA topoisomerase II inhibitor, etoposide (VP-16), which causes DNA single- and double-strand breaks [5,6], is employed as a therapeutic used in many types of cancers including lung cancer [7–9]. ARF, the product of an alternative open reading frame of the ARF/INK4 locus, is a tumor suppressor protein that is inactivated in lots of human tumors [10].
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Cytotoxicity of the topoisomerase II (topoII) poison etoposide has been ascribed to the persistent covalent trapping of topoII in DNA cleavage complexes that become lethal as cells replicate their DNA. However, short term etoposide treatment also leads to subsequent cell death, suggesting that the lesions that lead to cytotoxicity arise rapidly and prior to the onset DNA replication. In the present study 1 h treatment with 25 μM etoposide was highly toxic and initiated a double-stranded DNA damage response as reflected by the recruitment of ATM, MDC1 and DNA-PKcs to γH2AX foci. While most DNA breaks were rapidly repaired upon withdrawal of the etoposide treatment, the repair machinery remained engaged in foci for at least 24 h following withdrawal. TopoII siRNA ablation showed the etoposide toxicity and γH2AX response to correlate with the inability of the cell to correct topoIIα-initiated DNA damage. γH2AX induction was resistant to the inhibition of DNA replication and transcription, but was increased by pre-treatment with the histone deacetylase inhibitor trichostatin A. These results link the lethality of etoposide to the generation of persistent topoIIα-dependent DNA defects within topologically open chromatin domains.
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Despite the existence of a well described, succinct pathological grading system for gliomas, tumour behaviour between individual patients varies widely. In addition, predictors of response to treatment in glioblastoma multiforme are lacking. The majority of chemotherapeutic agents currently employed exert their effect on DNA. As our understanding of DNA repair mechanisms improves and predictive markers are elucidated, this may allow treating clinicians to individualise treatment based on molecular markers. This review examines important DNA repair mechanisms and their application to glioblastoma multiforme. By improving understanding of these mechanisms, and particularly the variations that occur between tumours and individuals, it may be possible to adapt treatment to maximise effectiveness and minimise toxicity.
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^☆: This work was supported by the Danish Cancer Society.

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CommentaryDNA topoisomerase II rescue by catalytic inhibitors: A new strategy to improve the antitumor selectivity of etoposide☆

Abstract

Lancet

Biochem Pharmacol

Biochem Pharmacol

Biochem Pharmacol

J Mol Biol

Biochem Pharmocol

Cell

Biochem Pharmacol

DNA topoisomerases—Essential enzymes and lethal targets

Annu Rev Pharmacol Toxicol

DNA topoisomerases

Annu Rev Biochem

Altered DNA topoisomerase II activity in Chinese hamster cells resistant to topoisomerase II inhibitors

Cancer Res

Altered catalytic activity of and DNA cleavage by DNA topoisomerase II from human leukemic cells selected for resistance to VM-26

Biochemistry

Lack of cross-resistance to fostriecin in a human small-cell lung carcinoma cell line showing topoisomerase II-related drug resistance

Cancer Chemother Pharmacol

DNA topoisomerase II is the molecular target of bisdioxopiperazine derivatives ICRF-159 and ICRF-193 in Saccharomyces cerevisiae

Cancer Res

Commentary
DNA topoisomerase II rescue by catalytic inhibitors: A new strategy to improve the antitumor selectivity of etoposide☆