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Aop: 279

AOP Title

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Microtubule interacting drugs lead to peripheral neuropathy

Short name:

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Microtubule interacting drugs lead to peripheral neuropathy

Graphical Representation

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Click to download graphical representation template

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Authors

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Anna Katharina Holzer, Stefan Schildknecht

Point of Contact

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Marvin Martens   (email point of contact)

Contributors

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  • Marvin Martens

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite


This AOP was last modified on January 29, 2019 08:51

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Revision dates for related pages

Page Revision Date/Time
Binding of microtubule stabilizing agents (MSA) to microtubules January 29, 2019 10:01
Disturbance in microtubule dynamic instability January 29, 2019 10:06
Impaired axonial transport January 29, 2019 10:07
Sensory axonal peripheral neuropathy January 29, 2019 10:08
Binding of MSAs to microtubules leads to Disturbance in microtubule dynamic instability January 29, 2019 10:10
Disturbance in microtubule dynamic instability leads to Impaired axonial transport January 29, 2019 10:11
Impaired axonial transport leads to Sensory axonal peripheral neuropathy January 29, 2019 10:12

Abstract

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Peripheral neuropathy is regularly observed as a side-effect in microtubule-targeted chemotherapies. The length of their axons, together with the absence of protection by a blood brain barrier, renders peripheral neurons particularly vulnerable to disturbances in microtubule dynamics.

The present AOP was developed to summarize mechanistic data that support the link between the interaction of “microtubule stabilizing agents” with microtubules (MIE) and sensory axonal peripheral neuropathy (AO), via disturbances in microtubule dynamic instability (KE1) and an impaired axonal transport (KE2).

The present AOP allowed the identification of the following knowledge gaps in the literature: (i) experimental support for the mechanistic link of microtubule interacting drugs with the onset of sensory axonal peripheral neuropathy is generally limited by laborious and circumstantial access to peripheral neurons in vivo and by limited availability of human in vitro models of peripheral neurons; (ii) it is necessary to distinguish the biological consequences of microtubule-stabilizing drugs on the one side, and microtubule-destabilizing compounds on the other; (iii) the link of clinical symptoms to the action of microtubule stabilizers is complicated by incomplete toxicokinetic data, by the time offset between drug treatment and clinical symptoms, and by partial reversibility of the AO following washout of the microtubule-interacting drugs.

The present AOP was developed to contribute to cross systems testing as well as to experimental studies covering the testing of National Toxicology Program compounds.


Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 MIE 1580 Binding of microtubule stabilizing agents (MSA) to microtubules Binding of MSAs to microtubules
2 KE 1581 Disturbance in microtubule dynamic instability Disturbance in microtubule dynamic instability
3 KE 1582 Impaired axonial transport Impaired axonial transport
4 AO 1583 Sensory axonal peripheral neuropathy Sensory axonal peripheral neuropathy

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Binding of MSAs to microtubules leads to Disturbance in microtubule dynamic instability adjacent Not Specified Not Specified
Disturbance in microtubule dynamic instability leads to Impaired axonial transport adjacent Not Specified Not Specified
Impaired axonial transport leads to Sensory axonal peripheral neuropathy adjacent Not Specified Not Specified

Network View

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Stressors

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Sex Applicability

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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