Identification of new candidate biomarkers to support doxorubicin treatments in canine cancer patients

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Both human and veterinary cancer chemotherapy are undergoing a paradigm shift from a “one size fits all” approach to more personalized, patient-oriented treatment strategies. Personalized chemotherapy is dependent on the identification and validation of biomarkers that can predict treatment outcome and/or risk of toxicity. Many cytotoxic chemotherapy agents, including doxorubicin, base their mechanism of action by interaction with DNA and disruption of normal cellular processes. We developed a high-resolution/accurate-mass liquid chromatography-mass spectrometry DNA screening approach for monitoring doxorubicin-induced DNA modifications (adducts) in vitro and in vivo. We used, for the first time, a new strategy involving the use of isotope-labeled DNA, which greatly facilitates adduct discovery. The overall goal of this work was to identify doxorubicin-DNA adducts to be used as biomarkers to predict drug efficacy for use in veterinary oncology. Results: We used our novel mass spectrometry approach to screen for adducts in purified DNA exposed to doxorubicin. This initial in vitro screening identified nine potential doxorubicin-DNA adduct masses, as well as an intense signal corresponding to DNA-intercalated doxorubicin. Two of the adduct masses, together with doxorubicin and its metabolite doxorubicinol, were subsequently detected in vivo in liver DNA extracted from mice exposed to doxorubicin. Finally, the presence of these adducts and analytes was explored in the DNA isolated from dogs undergoing treatment with doxorubicin. The previously identified nine DOX-DNA adducts were not detected in these preliminary three samples collected seven days post-treatment, however intercalated doxorubicin and doxorubicinol were detected. Conclusions: This work sets the stage for future evaluation of doxorubicin-DNA adducts and doxorubicin-related molecules as candidate biomarkers to personalize chemotherapy protocols for canine cancer patients. It demonstrates our ability to combine in one method the analysis of DNA adducts and DNA-intercalated doxorubicin and doxorubicinol. The last two analytes interestingly, were persistent in samples from canine patients undergoing doxorubicin chemotherapy seven days after treatment. The presence of doxorubicin in all samples suggests a role for it as a promising biomarker for use in veterinary chemotherapy. Future studies will involve the analysis of more samples from canine cancer patients to elucidate optimal timepoints for monitoring intercalated doxorubicin and doxorubicin-DNA adducts and the correlation of these markers with therapy outcome.

Original languageEnglish (US)
Article number378
JournalBMC Veterinary Research
Volume17
Issue number1
DOIs
StatePublished - Dec 2021

Bibliographical note

Funding Information:
The authors would like to thank the owners of the dogs for participating in this study. Additionally, the authors would like to extend thanks to the nurses at the University of Minnesota Veterinary Medical Center who collected the blood samples from the patients, to Romel P. Dator?and to?Alex Strom for providing the bacterial DNA?from E.coli obtained from The Coli Genetic Stock Center at Yale, and to Valeria Guidolin for providing data and insight regarding the use of the anticancer drug cyclophosphamide.

Funding Information:
This research was funded in part by the University of Minnesota Small Companion Animal Grant awarded to KW. BZ is supported by the National Heart, Lung, and Blood Institute, grant 1R01HL151740, the St. Baldrick’s Foundation for Childhood Cancer (Award ID 638335); and the National Institutes of Health’s National Center for Advancing Translational Sciences, grant UL1TR002494. The funders had no role in the design of the collection, analysis, and interpretation of data.

Publisher Copyright:
© 2021, The Author(s).

Keywords

  • Adductomics
  • DNA adducts
  • Doxorubicin
  • Precision medicine
  • Predictive biomarker
  • Veterinary oncology

PubMed: MeSH publication types

  • Journal Article

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