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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)102511-102520
Number of pages10
JournalOncotarget
Volume8
Issue number60
DOIs
StatePublished - Jan 1 2017

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Magnetic Resonance Imaging
Neoplasms
Pharmaceutical Preparations
Sulfhydryl Compounds
Reactive Nitrogen Species
Ewing's Sarcoma
Tumor Microenvironment
SCID Mice
RRx-001
Heterografts
Oxidants
Epigenomics
Serum Albumin
Antineoplastic Agents
Contrast Media
Colorectal Neoplasms
Reactive Oxygen Species
Perfusion
Biomarkers
Injections

Keywords

  • BOLD
  • Gadolinium
  • MRI
  • Redox
  • RRx-001

ASJC Scopus subject areas

  • Oncology

Cite this

Raghunand, N., Scicinski, J., Guntle, G. P., Jagadish, B., Mash, E. A., Bruckheimer, E., ... Korn, R. L. (2017). Magnetic resonance imaging of RRx-001 pharmacodynamics in preclinical tumors. Oncotarget, 8(60), 102511-102520. https://doi.org/10.18632/oncotarget.18455

Magnetic resonance imaging of RRx-001 pharmacodynamics in preclinical tumors. / Raghunand, Natarajan; Scicinski, Jan; Guntle, Gerald P.; Jagadish, Bhumasamudram; Mash, Eugene A; Bruckheimer, Elizabeth; Oronsky, Bryan; Korn, Ronald L.

In: Oncotarget, Vol. 8, No. 60, 01.01.2017, p. 102511-102520.

Research output: Contribution to journalArticle

Raghunand, N, Scicinski, J, Guntle, GP, Jagadish, B, Mash, EA, Bruckheimer, E, Oronsky, B & Korn, RL 2017, 'Magnetic resonance imaging of RRx-001 pharmacodynamics in preclinical tumors', Oncotarget, vol. 8, no. 60, pp. 102511-102520. https://doi.org/10.18632/oncotarget.18455
Raghunand N, Scicinski J, Guntle GP, Jagadish B, Mash EA, Bruckheimer E et al. Magnetic resonance imaging of RRx-001 pharmacodynamics in preclinical tumors. Oncotarget. 2017 Jan 1;8(60):102511-102520. https://doi.org/10.18632/oncotarget.18455
Raghunand, Natarajan ; Scicinski, Jan ; Guntle, Gerald P. ; Jagadish, Bhumasamudram ; Mash, Eugene A ; Bruckheimer, Elizabeth ; Oronsky, Bryan ; Korn, Ronald L. / Magnetic resonance imaging of RRx-001 pharmacodynamics in preclinical tumors. In: Oncotarget. 2017 ; Vol. 8, No. 60. pp. 102511-102520.
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