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Therapy

Serial monitoring of human systemic and xenograft models of leukemia using a novel vascular disrupting agent

Leukemia volume 26, pages 1771–1778 (2012)Cite this article

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Abstract

Advances in the treatment of acute leukemia have resulted in significantly improved remission rates, although disease relapse poses a significant risk. By utilizing sensitive, non-invasive imaging guidance, detection of early leukemic infiltration and the extent of residual tumor burden after targeted therapy can be expedited, leading to more efficient treatment planning. We demonstrated marked survival benefit and therapeutic efficacy of a new-generation vascular disrupting agent, combretastatin-A1-diphosphate (OXi4503), using reporter gene-imaging technologies and mice systemically administered luc+ and GFP+ human leukemic cells (LCs). Before treatment, homing of double-transduced cells was serially monitored and whole-body cellular distributions were mapped using bioluminescence imaging (BLI). Imaging findings strongly correlated with quantitative GFP expression levels in solid organs/tissues, suggesting that the measured BLI signal provides a highly sensitive and reliable biomarker of tumor tissue burden in systemic leukemic models. Such optical technologies can thereby serve as robust non-invasive imaging tools for preclinical drug discovery and for rapidly screening promising therapeutic agents to establish potency, treatment efficacy and survival advantage. We further show that GFP+ HL-60 cells reside in close proximity to VE-cadherin- and CD31-expressing endothelial cells, suggesting that the perivascular niche may have a critical role in the maintenance and survival of LCs.

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Acknowledgements

We acknowledge M Gönen for providing assistance with biostatistical analyses and L Johnson in the Laboratory of Comparative Pathology for assistance with interpretation of histological specimens. This study was supported in part by an ICMIC P50 CA86438 grant. Technical services provided by the MSKCC Small-Animal Imaging Core Facility, supported in part by NIH Small-Animal Imaging Research Program (SAIRP) Grant No R24 CA83084 and NIH Center Grant No P30 CA08748, are gratefully acknowledged.

Author information

Author notes

  1. K Dobrenkov

    Present address: 5Current address: Lincoln Medical and Mental Health Center, Bronx, NY 10451, USA.,

  2. S Rabbany and M S Bradbury: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, NY, USA

    M Benezra, E Phillips, K Dobrenkov & M S Bradbury

  2. Ansary Stem Cell Institute and Department of Genetic Medicine, Howard Hughes Medical Institute, Weill Cornell Medical College, New York, NY, USA

    D Tilki, B-S Ding, J Butler, S Rafii & S Rabbany

  3. OXiGENE, Inc., South San Francisco, CA, USA

    B Siim & D Chaplin

  4. Bioengineering Program, Hofstra University, Hempstead, NY, USA

    S Rabbany

Authors
  1. M Benezra
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Corresponding author

Correspondence to M S Bradbury.

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Competing interests

DC is currently the Head of Research and Development at OXiGENE. BS previously held the position of Director of Research at OXiGENE, but is no longer at the company. The remaining authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Leukemia website

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Benezra, M., Phillips, E., Tilki, D. et al. Serial monitoring of human systemic and xenograft models of leukemia using a novel vascular disrupting agent. Leukemia 26, 1771–1778 (2012). https://doi.org/10.1038/leu.2012.48

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