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PMID: 16459166 Published · ppublish English Clinical Trial, Phase I Journal Article Research Support, N.I.H., Extramural

The antitumor thioredoxin-1 inhibitor PX-12 (1-methylpropyl 2-imidazolyl disulfide) decreases thioredoxin-1 and VEGF levels in cancer patient plasma.

The Journal of laboratory and clinical medicine ·Vol. 147 ·No. 2 ·2006-02-00 ·Pages 83-90

Baker AF, Dragovich T, Tate WR, Ramanathan RK, Roe D, Hsu CH, Kirkpatrick DL, Powis G

Abstract

Thioredoxin-1 (Trx-1) is a small redox protein that is overexpressed in many human tumors, where it is associated with aggressive tumor growth and decreased patient survival. Trx-1 is secreted by tumor cells and is present at increased levels in the plasma of cancer patients. PX-12 is an irreversible inhibitor of Trx-1 currently in clinical development as an antitumor agent. We have used SELDI-TOF mass spectroscopy to measure plasma Trx-1 from patients treated with PX-12 during a phase I study. Mean plasma Trx-1 levels at pretreatment were significantly elevated in the cancer patients at 182.0 ng/mL compared with 27.1 ng/mL in plasma from healthy volunteers. PX-12 treatment significantly lowered plasma Trx-1 in cancer patients having the highest plasma Trx-1 pretreatment levels. High-plasma vascular endothelial growth factor (VEGF) levels have been correlated to decreased patient survival. PX-12 treatment also significantly lowered plasma VEGF levels in cancer patients with high pretreatment VEGF levels. SELDI-TOF mass spectrometry identified seven additional plasma proteins whose levels decreased after PX-12 administration, one of which was identified as a truncated form of transthyretin. The results of this study suggest that the lowering of elevated levels of plasma Trx-1 in cancer patients may provide a surrogate for the inhibition of tumor Trx-1 by PX-12. Furthermore, PX-12 decreases plasma VEGF levels that may contribute to the antitumor activity of PX-12.

MeSH Terms
Animals Antineoplastic Agents/administration & dosage,pharmacology Disulfides/administration & dosage,pharmacology Drug Monitoring/instrumentation,methods Humans Imidazoles/administration & dosage,pharmacology Male Mice Mice, Inbred C57BL Neoplasms/blood,drug therapy Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Thioredoxins/antagonists & inhibitors,blood Vascular Endothelial Growth Factor A/blood
Chemicals
Antineoplastic Agents Disulfides Imidazoles TXN protein, human VEGFA protein, human Vascular Endothelial Growth Factor A vascular endothelial growth factor A, mouse Thioredoxins 1-methylpropyl-2-imidazolyl disulfide
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Baker Amanda F
Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA.
Dragovich Tomislav
Tate Wendy R
Ramanathan Ramesh K
Roe Denise
Hsu Chiu-Hsieh
Kirkpatrick D Lynn
Powis Garth
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Article Info
Journal
The Journal of laboratory and clinical medicine
Abbr.
J Lab Clin Med
ISSN
0022-2143
DOI
10.1016/j.lab.2005.09.001
Published
2006-02-00
Pages
83-90
Language
English
Region
United States
NLM ID
0375375
PMCID
PMC1432091
Subset
IM
Grants
NCI NIH HHS · P30 CA023074 · United States
NCI NIH HHS · R01 CA098920 · United States
NCI NIH HHS · CA17094 · United States
NCI NIH HHS · U54 CA090821 · United States
NCI NIH HHS · P01 CA017094 · United States
NCI NIH HHS · CA090824 · United States
NCI NIH HHS · CA023074 · United States
NCI NIH HHS · R01 CA077204 · United States
External Links
PubMed source DOI: 10.1016/j.lab.2005.09.001 PMC Full Text
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