Oncotarget

Clinical Research Papers:

Magnetic resonance imaging of RRx-001 pharmacodynamics in preclinical tumors

Natarajan Raghunand _, Jan Scicinski, Gerald P. Guntle, Bhumasamudram Jagadish, Eugene A. Mash, Elizabeth Bruckheimer, Bryan Oronsky, Ronald L. Korn

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Oncotarget. 2017; 8:102511-102520. https://doi.org/10.18632/oncotarget.18455

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Abstract

Natarajan Raghunand1, Jan Scicinski2, Gerald P. Guntle3, Bhumasamudram Jagadish4, Eugene A. Mash4, Elizabeth Bruckheimer5, Bryan Oronsky2 and Ronald L. Korn5

1Moffitt Cancer Center, Tampa, Florida, USA

2EpicentRx, Inc., San Diego, California, USA

3Arizona Cancer Center, The University of Arizona, Tucson, Arizona, USA

4Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona, USA

5Imaging Endpoints LLC, Scottsdale, Arizona, USA

Correspondence to:

Natarajan Raghunand, email: Natarajan.Raghunand@moffitt.org

Keywords: RRx-001, gadolinium, MRI, redox, BOLD

Received: August 15, 2016     Accepted: May 22, 2017     Published: June 12, 2017

ABSTRACT

RRx-001 is an anticancer agent that subjects cancer cells to reactive oxygen/nitrogen species (ROS/RNS) and acts as an epigenetic modifier. We have used a thiol-bearing MRI contrast agent, Gd-LC7-SH, to investigate the pharmacodynamics of RRx-001 in CHP-100 Ewing’s Sarcoma, HT-29 colorectal carcinoma, and PANC-1 pancreatic carcinoma xenografts in SCID mice. Binding of Gd-LC7-SH to the Cys34 residue on plasma albumin prolongs retention in the tumor microenvironment and increases tumor enhancement on MRI. Mice were imaged by MRI and in vivo T1 maps acquired 50 min (T150 min) after injection of 0.05 mmol/kg Gd-LC7-SH (i.v.) at baseline and 1, 24, and 72 h post-treatment with 10 mg/kg RRx-001 (i.v.). Consistent with an indirect thiol-modifying activity of RRx-001, tumor T150 min at 1 h post-drug was significantly longer than pre-drug tumor T150 min in all three tumor models, with the T150 min remaining significantly longer than baseline through 72 h post-drug in the HT-29 and PANC-1 tumors. The T150 min of CHP-100 tumors recovered to baseline by 24 h post-drug, suggesting a robust anti-oxidant response to the RRx-001 challenge that was presaged by a marked increase in perfusion at 1 h post-drug measured by DCE-MRI. MRI enhanced with Gd-LC7-SH provides a mechanistically rational biomarker of RRx-001 pharmacodynamics.


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