Whole-body imaging of cell death provides a systemic, minimally invasive, dynamic, and near-real time indicator for chemotherapeutic drug toxicity

Steven E. Johnson, Andrey Ugolkov, Chad R. Haney, Gennadiy Bondarenko, Lin Li, Emily A. Waters, Raymond Bergan, Andy Tran, Thomas V. O'Halloran, Andrew Mazar, Ming Zhao

Research output: Contribution to journalArticle

Abstract

Purpose: Response to toxicity in chemotherapies varies considerably from tissue to tissue and from patient to patient. An ability to monitor the tissue damage done by chemotherapy may have a profound impact on treatment and prognosis allowing for a proactive management in understanding and mitigating such events. For the first time, we investigated the feasibility of using whole-body imaging to map chemotherapeutic drug–induced toxicity on an individual basis. Experimental Design: In a preclinical proof-of-concept, rats were treated with a single clinical dose of cyclophosphamide, methotrexate, or cisplatin. In vivo whole-body imaging data were acquired using 99m Tc-duramycin, which identifies dead and dying cells as an unambiguous marker for tissue injury in susceptible organs. Imaging results were cross-validated using quantitative ex vivo measurements and histopathology and compared with standard blood and serum panels for toxicology. Results: The in vivo whole-body imaging data detected widespread changes, where spatially heterogeneous toxic effects were identified across different tissues, within substructures of organs, as well as among different individuals. The signal changes were consistent with established toxicity profiles of these chemotherapeutic drugs. Apart from generating a map of susceptible tissues, this in vivo imaging approach was more sensitive compared with conventional blood and serum markers used in toxicology. Also, repeated imaging during the acute period after drug treatment captured different kinetics of tissue injury among susceptible organs in males and females. Conclusions: This novel and highly translational imaging approach shows promise in optimizing therapeutic decisions by detecting and managing drug toxicity on a personalized basis. Toxicity to normal tissues is a significant limitation in chemotherapies. This work demonstrated an in vivo imaging-based approach for characterizing toxicity-induced tissue injury in a systemic, dynamic, and near-real time fashion. This novel approach shows promise in optimizing therapeutic decisions by monitoring drug toxicity on a personalized basis.

Original languageEnglish (US)
Pages (from-to)1331-1342
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number4
DOIs
StatePublished - Feb 15 2019

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Whole Body Imaging
Drug-Related Side Effects and Adverse Reactions
Cell Death
Drug Therapy
Toxicology
Wounds and Injuries
Poisons
Therapeutics
Serum
Methotrexate
Pharmaceutical Preparations
Cyclophosphamide
Cisplatin
Research Design
Biomarkers

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Whole-body imaging of cell death provides a systemic, minimally invasive, dynamic, and near-real time indicator for chemotherapeutic drug toxicity. / Johnson, Steven E.; Ugolkov, Andrey; Haney, Chad R.; Bondarenko, Gennadiy; Li, Lin; Waters, Emily A.; Bergan, Raymond; Tran, Andy; O'Halloran, Thomas V.; Mazar, Andrew; Zhao, Ming.

In: Clinical Cancer Research, Vol. 25, No. 4, 15.02.2019, p. 1331-1342.

Research output: Contribution to journalArticle

Johnson, SE, Ugolkov, A, Haney, CR, Bondarenko, G, Li, L, Waters, EA, Bergan, R, Tran, A, O'Halloran, TV, Mazar, A & Zhao, M 2019, 'Whole-body imaging of cell death provides a systemic, minimally invasive, dynamic, and near-real time indicator for chemotherapeutic drug toxicity', Clinical Cancer Research, vol. 25, no. 4, pp. 1331-1342. https://doi.org/10.1158/1078-0432.CCR-18-1846
Johnson, Steven E. ; Ugolkov, Andrey ; Haney, Chad R. ; Bondarenko, Gennadiy ; Li, Lin ; Waters, Emily A. ; Bergan, Raymond ; Tran, Andy ; O'Halloran, Thomas V. ; Mazar, Andrew ; Zhao, Ming. / Whole-body imaging of cell death provides a systemic, minimally invasive, dynamic, and near-real time indicator for chemotherapeutic drug toxicity. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 4. pp. 1331-1342.
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AU - Li, Lin

AU - Waters, Emily A.

AU - Bergan, Raymond

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AU - O'Halloran, Thomas V.

AU - Mazar, Andrew

AU - Zhao, Ming

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