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Updated: May 8, 2026
Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
Optical imaging of treatment-related tumor cell death using a heat shock protein-90 alkylator
Danielle Park1, Bang-Wen Xie, Ermond R Van Beek
1Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales , Sydney, New South Wales 2052, Australia.
Abstract:
The ability to assess in near-real time the tumor cell killing efficacy of chemotherapy regimens would improve patient treatment and survival. An ineffective regimen could be abandoned early in favor of a more effective treatment. We sought to noninvasively image treatment-related tumor cell death in mice using an optically labeled synthetic heat shock protein-90 (Hsp90) alkylator, 4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid (GSAO). The Hsp90 chaperone is an important element in oncogene addiction and tumor cell survival, and its expression is enhanced by chemotherapy. These factors were predicted to favor the detection of tumor cell death using GSAO. GSAO specifically labeled apoptotic and necrotic tumor cells in culture and cells of comparable morphology in subcutaneous human pancreatic carcinoma tumors in mice. A near-infrared fluorescent conjugate of GSAO was used to noninvasively image cyclophosphamide-induced tumor cell death in murine orthotopic human mammary tumors. The GSAO conjugate did not accumulate in healthy organs or tissues in the mouse, and unbound compound was excreted rapidly via the kidneys. There was a significant increase in the GSAO fluorescence signal in the treated tumors measured either in vivo or ex vivo, and the fluorescence signal colocalized with apoptotic cells in sectioned tumors. The favorable biodistribution of optically labeled GSAO, the nature of its tumor cell target, and its capacity to noninvasively detect tumor cell death should facilitate the application of this compound in studies of the efficacy of existing and new chemotherapeutics.
Insights
This study introduces an optically labeled compound, GSAO, to noninvasively image chemotherapy-induced tumor cell death in mice. This method allows for near-real-time assessment of treatment efficacy, potentially improving patient outcomes.
Area of Science:
- Oncology
- Molecular Imaging
- Drug Discovery
Background:
- Assessing chemotherapy efficacy in real-time is crucial for improving patient survival.
- Ineffective treatments could be identified early, allowing for timely switching to alternative therapies.
- Heat shock protein-90 (Hsp90) is vital for tumor cell survival and its expression increases with chemotherapy.
Purpose of the Study:
- To develop a noninvasive imaging method to assess chemotherapy-induced tumor cell death.
- To evaluate the efficacy of an optically labeled Hsp90 alkylator, GSAO, for imaging tumor cell death in vivo.
- To determine the biodistribution and excretion profile of the GSAO conjugate.
Main Methods:
- Utilized an optically labeled synthetic Hsp90 alkylator, 4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid (GSAO).
- Administered a near-infrared fluorescent GSAO conjugate to mice with induced tumors.
- Performed noninvasive imaging of tumor cell death in murine models.
- Analyzed GSAO fluorescence signal in vivo and ex vivo, and correlated with apoptotic cells.
Main Results:
- GSAO specifically labeled apoptotic and necrotic tumor cells in vitro and in vivo.
- Noninvasive imaging revealed increased GSAO fluorescence in treated tumors, indicating cell death.
- The GSAO conjugate exhibited favorable biodistribution, with rapid renal excretion and minimal accumulation in healthy tissues.
- Fluorescence signal colocalized with apoptotic cells in sectioned tumors.
Conclusions:
- Optically labeled GSAO enables noninvasive detection of chemotherapy-induced tumor cell death.
- The compound's specific targeting and favorable pharmacokinetics support its use in evaluating chemotherapeutic efficacy.
- This imaging approach has the potential to guide treatment decisions and improve patient outcomes.
