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dc.contributor.authorRaghunand, Natarajan
dc.contributor.authorScicinski, Jan
dc.contributor.authorGuntle, Gerald P.
dc.contributor.authorJagadish, Bhumasamudram
dc.contributor.authorMash, Eugene A.
dc.contributor.authorBruckheimer, Elizabeth
dc.contributor.authorOronsky, Bryan
dc.contributor.authorKorn, Ronald L.
dc.date.accessioned2018-03-15T23:20:54Z
dc.date.available2018-03-15T23:20:54Z
dc.date.issued2017-06-13
dc.identifier.citationMagnetic resonance imaging of RRx-001 pharmacodynamics in preclinical tumors 2017, 8 (60) Oncotargeten
dc.identifier.issn1949-2553
dc.identifier.pmid29254266
dc.identifier.doi10.18632/oncotarget.18455
dc.identifier.urihttp://hdl.handle.net/10150/627064
dc.description.abstractRRx-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 (T1(50 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.
dc.description.sponsorshipEpicentRx; National Institutes of Health [R01-CA118359, P30-CA023074]en
dc.language.isoenen
dc.publisherIMPACT JOURNALS LLCen
dc.relation.urlhttp://www.oncotarget.com/fulltext/18455en
dc.rights© Raghunand et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0).en
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/
dc.subjectRRx-001en
dc.subjectgadoliniumen
dc.subjectMRIen
dc.subjectredoxen
dc.subjectBOLDen
dc.titleMagnetic resonance imaging of RRx-001 pharmacodynamics in preclinical tumorsen
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Arizona Canc Ctren
dc.contributor.departmentUniv Arizona, Dept Chem & Biochemen
dc.identifier.journalOncotargeten
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
refterms.dateFOA2018-06-25T17:34:16Z
html.description.abstractRRx-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 (T1(50 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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© Raghunand et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0).
Except where otherwise noted, this item's license is described as © Raghunand et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0).