API

Stressor: 223

Title

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Etoposide

Stressor Overview

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AOPs Including This Stressor

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Events Including This Stressor

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Chemical Table

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The Chemical Table lists chemicals associated with a stressor. This table contains information about the User’s term for a chemical, the DTXID, Preferred name, CAS number, JChem InChIKey, and Indigo InChIKey.

Instructions

To add a chemical associated with a particular stressor, next to the Chemical Table click ‘Add chemical.’ This will redirect you to a page entitled “New Stressor Chemical.’ The dialog box can be used to search for chemical by name, CAS number, JChem InChIKey, and Indigo InChIKey. Searching by these fields will bring forward a drop down list of existing stressor chemicals formatted as “CAS- preferred name” “JChem InChIKey – preferred name” or “Indigo InChIKey- preferred name” depending on which field you perform the search. Select an entity from the drop down list and click ‘Add chemical.’ This will return you to the Stressor Page, where the new record should be in the ‘Chemical Table’ on the page.


AOP Evidence

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In-utero DNA topoisomerase II poisons leading to infant leukaemia

A number of drugs, environmental chemicals and natural substances are identified as TopoII “poisons” (Pendleton et al 2014) . A well investigated example   is the anticancer drug etoposide; also bioflavonoids, e.g. genistein, (Barjesteh van Waalwijk van Doorn-Khosrovani et al 2007; Azarova et al 2010) bind to TopoII enzymes, induce cleavage in the MLL gene and produce a fusion gene (and its product) in human cells. The organophosphate pesticide chlorpyrifos has been shown to inhibit (‘poison’) the enzyme in vitro (Lu et al 2015).

Chemical class

Examples

References

Anticancer agents

Epipodophyllotoxins

etoposide, teniposide

Montecucco et al 2015

Anthracyclines

doxorubicin, epirubicin, daunorubicin, idarubicin, aclarubicin

Cowell and Austin 2012

Anthacenedione

Mitoxantrone

Cowell and Austin 2012

Acridines

Amsacrine

Cowell and Austin 2012

Much of the relevant, albeit  indirect, evidence to support this AOP come from the studies on etoposide, an anticancer drug  TopoII “poison”, which is known to induce therapy-associated acute leukaemia (t-AL) in adults (Cowell and Austin 2012; Pendleton et al 2014). It is of interest that the latency of t-AL is <2 years between the treatment of the primary malignancy and the clinical diagnosis of the secondary disease and that the prognosis of t-AL is poor (Pendleton et al 2014). t-AL is characterized by the MLL rearrangements and it is practically certain that these fusion genes are caused by etoposide or anthracyclines treatment, because MLL rearrangements have not been detected in bone marrow samples banked before the start of the treatment of the first malignancy. Also the breakpoints in MLL or partner genes fall within a few base pairs of a drug-induced enzyme-mediated DNA cleavage site (Pendleton et al 2014).

Etoposide can induce MLL rearrangements in different cell types; interestingly, embryonic stem cells and their hematopoietic derivatives are much more sensitive than cord blood-derived CD34+ cells to etoposide induced MLL rearrangements; in addition, undifferentiated human embryonic stem cells (hESCs) were concurrently liable to acute cell death (Bueno et al., 2009). These findings suggest that the MIE should be put into evidence in target cell models with appropriate sensitivity. 




Event Evidence

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In utero MLL chromosomal translocation

There is abundant evidence on the interaction of etoposide with topo II enzymes, resulting in further chromosomal translocations (in particular MLL-r) at the cell culture level and in relation to treatment-related leukaemia (Cowell and Austin, 2012; Ezoe, 2012; Pendleton and Osheroff, 2014; Gole and Wiesmuller, 2015). Etoposide can induce MLL-r in different cell types. Interestingly, embryonic stem cells and their hematopoietic derivatives are much more sensitive than cord blood-derived CD34+ cells to etoposide induced MLL-r. In addition, undifferentiated human embryonic stem cells (hESCs) were concurrently predisposed to acute cell death (Bueno et al., 2009).  Molecular dose-response modelling of etoposide-induced DNA damage response, based on comprehensive in vitro high content imaging in the HT1080 cell model, was developed by Li et al. (2014).  



Infant leukaemia

Topo II is a well validated anti-cancer target and Topo II poisons are widely used and effective therapeutic agents; but they are associated with the occurence of late complications, including therapy-related acute leukaemia (Cowell and Austin, 2012). Secondary acute leukaemia carrying MLL-r is an adverse effect observed in patients treated with etoposide and a few other anticancer agents. Characteristics of the disease are in many ways analogous to those in infant leukaemia (Joannides et al., 2010, 2011). MLL rearrangement, short latency and poor prognosis, strongly suggest that infant leukaemia and treatment-related leukaemia are sufficiently similar to allow for inferences to be made regarding tentative aetiological factors, molecular events and disease progression and manifestation.

 

 



In-utero DNA topoisomerase II “poisons-

Etoposide is one of the most well studied topoisomerase II-targeted agents in clinical use. The drug stabilizes covalent topoisomerase II-cleaved DNA complexes (i.e., cleavage complexes) by interacting at the enzyme–DNA interface in a noncovalent manner. Once the double helix is cut, the drug slips (i.e., intercalates) between the 3′-hydroxyl and the enzyme-linked 5′-phosphate at the cleaved scissile bond and acts as a physical block to topoisomerase II-mediated DNA ligation. Etoposide and other drugs that utilize this mechanism are termed “interfacial topoisomerase II poisons”. The catechol displayed properties that were similar to those of the parent drug and appeared to be an interfacial poison. The properties of the quinone metabolite differed from those of etoposide, and the quinone appeared to function by a different mechanism. Previous studies with quinones and other protein-reactive agents have found that some of these compounds increase levels of topoisomerase II-mediated DNA cleavage by covalently adducting to the enzyme at residues that are distal to the active site.Thus, these agents are termed “covalent topoisomerase II poisons”. It is believed that covalent poisons enhance DNA cleavage, at least in part, by closing the N-terminal gate of the protein. Several lines of evidence suggest that etoposide quinone poisons topoisomerase II by this latter, covalent mechanism (Smith NA, 2014).

 




Stressor Info

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Chemical/Category Description

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Instructions

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Characterization of Exposure

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Instructions

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References

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List the bibliographic references to original papers, books or other documents used to support the Stressor.

Instructions

To edit the “References” section, on a Stressor page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Stressor.”  Scroll down to the “References” section, where a text entry box allows you to submit text. Click ‘Update’ to save your changes and return to the Stressor page.  The new text should appear under the “References” section on the page.