What question did this study set out to answer?

To determine whether mitochondrial topoisomerase 1 (Top1mt) protects cardiac tissue against doxorubicin-induced mitochondrial dysfunction and heart failure.

April 9, 2014Clinical Cancer ResearchOpen Access

Mitochondrial Topoisomerase I (Top1mt) Is a Novel Limiting Factor of Doxorubicin Cardiotoxicity

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Why the study?

Does Top1mt knockout increase susceptibility to doxorubicin-induced cardiotoxicity in mice?

Population

Wild-type (WT) and mitochondrial topoisomerase 1 (Top1mt) knockout (KO) mice

Comparison

Doxorubicin 4 mg/kg once a week for 8 weeks vs Wild-type mice treated with the same doxorubicin…

Design

Preclinical

Follow-up

Up to 45 days after the last doxorubicin injection

Authors

SKSalim KhiatiCentre National de la Recherche Scientifique IRIlaria Dalla RosaThe Francis Crick Institute CSCarole SourbierCenter for Drug Evaluation and Research

Discussion

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Implication

Top1mt loss heightens doxorubicin cardiotoxicity mortality in mice; leaves open its value as a human susceptibility marker.

Key Points

To determine whether mitochondrial topoisomerase 1 (Top1mt) protects cardiac tissue against doxorubicin-induced mitochondrial dysfunction and heart failure.
Administered 4 mg/kg doxorubicin weekly for 8 weeks to wild-type and Top1mt-knockout mice.
Evaluated cardiac tissue histology, mtDNA integrity, respiratory chain protein expression, mitochondrial ultrastructure, and overall survival after treatment.
Top1mt-knockout mice displayed exacerbated mtDNA copy number loss, extensive mtDNA damage, disrupted mitochondrial cristae, and impaired respiratory chain protein synthesis following doxorubicin exposure.
Deficiency in Top1mt led to reduced oxygen consumption, increased reactive oxygen species production, heightened cardiac muscle damage, and 100% mortality within 45 days post-treatment compared to full survival in wild-type mice.

Structured PICO

Does Top1mt knockout increase susceptibility to doxorubicin-induced cardiotoxicity in mice?

Population

Wild-type (WT) and mitochondrial topoisomerase 1 (Top1mt) knockout (KO) mice

Intervention

Doxorubicin 4 mg/kg once a week for 8 weeks

Comparator

Wild-type (WT) mice treated with the same doxorubicin regimen

Outcome

mtDNA copy number loss, mtDNA damage, mitochondrial defects, heart muscle damage, and survivalsurrogate

Top1mt is critical for cardiac tolerance to doxorubicin, suggesting its potential as a genetic marker for susceptibility to doxorubicin-induced cardiotoxicity.

Cite This Study

Khiati et al. (2014) studied this question.

synapsesocial.com/papers/6a7025fa35aa2c282ce17412 https://doi.org/10.1158/1078-0432.ccr-13-3373

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Mitochondrial Topoisomerase I (Top1mt) Is a Novel Limiting Factor of Doxorubicin Cardiotoxicity

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

Mitochondrial Topoisomerase I (Top1mt) Is a Novel Limiting Factor of Doxorubicin Cardiotoxicity

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

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Also Consider