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Monitoring antivascular therapy in head and neck cancer xenografts using contrast-enhanced MR and US imaging

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Abstract

Background

The overall goal of this study was to non-invasively monitor changes in blood flow of squamous cell carcinoma of the head and neck (SCCHN) xenografts using contrast-enhanced magnetic resonance (MR) and ultrasound (US) imaging.

Methods

Experimental studies were performed on mice bearing FaDu tumors and SCCHN xenografts derived from human surgical tissue. MR examinations were performed using gadofosveset trisodium at 4.7T. Change in T1-relaxation rate of tumors (ΔR1) and tumor enhancement parameters (amplitude, area under the curve—AUC) were measured at baseline and 24 h after treatment with a tumor-vascular disrupting agent (tumor-VDA), 5,6-dimethylxanthenone-4-acetic acid (DMXAA; ASA404) and correlated with tumor necrosis and treatment outcome. CE-US was performed using microbubbles (Vevo MicroMarker®) to assess the change in relative tumor blood volume following VDA treatment.

Results

A marked decrease (up to 68% of baseline) in T1-enhancement of FaDu tumors was observed 1 day after VDA therapy indicative of a reduction in blood flow. Early (24 h) vascular response of individual tumors to VDA therapy detected by MRI correlated with tumor necrosis and volume estimates at 10 days post treatment. VDA treatment also resulted in a significant reduction in AUC and amplitude of patient tumor-derived SCCHN xenografts. Consistent with MRI observations, CE-US revealed a significant reduction in tumor blood volume of patient tumor-derived SCCHN xenografts after VDA therapy. Treatment with VDA resulted in a significant tumor growth inhibition of patient tumor derived SCCHN xenografts.

Conclusions

These findings demonstrate that both CE-MRI and CE-US allow monitoring of early changes in vascular function following VDA therapy. The results also demonstrate, for the first time, potent vascular disruptive and antitumor activity of DMXAA against patient tumor-derived head and neck carcinoma xenografts.

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Abbreviations

CE-MRI:

Contrast-enhanced magnetic resonance imaging

CE-US:

Contrast-enhanced ultrasound

SCCHN:

Squamous cell carcinoma xenografts

VDA:

Vascular disrupting agent

DMXAA:

5,6-Dimethylxanthenone-4-acetic acid

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Acknowledgments

The authors would like to thank Mr. Steve Turowski and Ms. Jaimee Lockwood for their assistance in performing the imaging studies. This work was supported by grants from the National Cancer Institute R21CA133688 (M.S.) and utilized core resources supported by RPCI’s Cancer Center Support Grant from the NCI P30CA16056 (Trump, DL).

Conflicts of interest

Seshadri M: None; Sacadura NT is a full-time employee of VisualSonics Inc.; Coulthard T was a full-time employee of VisualSonics Inc. during the period the study. Currently an employee at Aspect Imaging, Toronto, ON, Canada.

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Author notes

  1. Tonya Coulthard

    Present address: Aspect Imaging, Toronto, ON, Canada

Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, Preclinical Imaging Laboratory, Roswell Park Cancer Institute, Buffalo, NY, USA

    Mukund Seshadri

  2. Department of Dentistry and Maxillofacial Prosthetics, Roswell Park Cancer Institute, Buffalo, NY, USA

    Mukund Seshadri

  3. VisualSonics Inc., Toronto, ON, Canada

    Nuno T. Sacadura & Tonya Coulthard

Authors
  1. Mukund Seshadri
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  2. Nuno T. Sacadura
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  3. Tonya Coulthard
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Correspondence to Mukund Seshadri.

Electronic supplementary material

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10456_2011_9233_MOESM1_ESM.ppt

S1. Photomicrographs of H&E stained FaDu tumor sections on day 10 post VDA treatment. S2. Change in R1 (ΔR1) of FaDu tumors and blood (vessel) following administration of gadopentetate and gadofosveset. (PPT 18113 kb)

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Seshadri, M., Sacadura, N.T. & Coulthard, T. Monitoring antivascular therapy in head and neck cancer xenografts using contrast-enhanced MR and US imaging. Angiogenesis 14, 491–501 (2011). https://doi.org/10.1007/s10456-011-9233-1

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  • DOI: https://doi.org/10.1007/s10456-011-9233-1

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