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J Lab Clin Med. 2006 Feb;147(2):83-90.

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

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1
Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA.

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.

PMID:
16459166
PMCID:
PMC1432091
DOI:
10.1016/j.lab.2005.09.001
[Indexed for MEDLINE]
Free PMC Article
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