The thioredoxin-1 inhibitor 1-methylpropyl 2-imidazolyl disulfide (PX-12) decreases vascular permeability in tumor xenografts monitored by dynamic contrast enhanced magnetic resonance imaging.
OBJECTIVE
The purpose of this study was to use dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to measure changes in tumor xenograft permeability produced by the antitumor thioredoxin-1 (Trx-1) inhibitor 1-methylpropyl 2-imidazolyl disulfide (PX-12) and to assess the relationship to Trx-1 and vascular endothelial growth factor (VEGF) levels.


METHODS
DCE-MRI was used to monitor the dynamics of gadolinium-diethylenetriaminepentaacetic acid coupled bovine serum albumin as a macromolecular contrast reagent to measure hemodynamic changes in HT-29 human colon xenografts in immunodeficient mice treated with PX-12. Blood vessel permeability was estimated from the slope of the enhancement curves, and tumor vascular volume fraction from the ordinate. Tumor Trx-1 and VEGF was also measured.


RESULTS
PX-12 caused a rapid 63% decrease in the average tumor blood vessel permeability within 2 hours of administration. The decrease lasted 24 hours and had returned to pretreatment values by 48 hours. The changes in vascular permeability were not accompanied by alterations in average tumor vascular volume fraction. There was a decrease in tumor and tumor-derived VEGF in plasma at 24 hours after treatment with PX-12, but not at earlier time points. However, tumor redox active Trx-1 showed a rapid decline within 2 hours following PX-12 administration that was maintained for 24 hours.


CONCLUSIONS
The rapid decrease in tumor vascular permeability caused by PX-12 administration coincided with a decrease in tumor redox active Trx-1 and preceded a decrease in VEGF. DCE-MRI responses to PX-12 in patients of Trx-1 inhibition at early time points and decreased VEGF at later times, may be useful to follow tumor response and even therapeutic benefit.
Jordan
Bénédicte F
BF
Department of Biochemistry, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
Runquist
Matthew
M
Raghunand
Natarajan
N
Gillies
Robert J
RJ
Tate
Wendy R
WR
Powis
Garth
G
Baker
Amanda F
AF
D000418:Albumins; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D003287:Contrast Media; D004220:Disulfides / Q000494:pharmacology*; D005260:Female; D019786:Gadolinium DTPA; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D051379:Mice; D016513:Mice, SCID; D010084:Oxidation-Reduction; D013879:Thioredoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000418:Albumins; D003287:Contrast Media; D004220:Disulfides; D007093:Imidazoles; C491203:TXN protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C058946:albumin-(gadolinium-DTPA); D013879:Thioredoxins; C412893:1-methylpropyl-2-imidazolyl disulfide; D019786:Gadolinium DTPA