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

Amanda F Baker, Tomislav Dragovich, Wendy R. Tate, Ramesh K. Ramanathan, Denise Roe, Chiu-Hsieh Hsu, D. Lynn Kirkpatrick, Garth Powis

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)83-90
Number of pages8
JournalThe Journal of Laboratory and Clinical Medicine
Volume147
Issue number2
DOIs
StatePublished - Feb 2006
Externally publishedYes

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Thioredoxins
Vascular Endothelial Growth Factor A
Plasmas
Neoplasms
Tumors
Mass Spectrometry
IV 2 compound
Prealbumin
Survival
Antineoplastic Agents
Oxidation-Reduction
Mass spectrometry
Blood Proteins
Healthy Volunteers
Cells
Spectroscopy

ASJC Scopus subject areas

  • Medicine(all)
  • Pathology and Forensic Medicine

Cite this

The antitumor thioredoxin-1 inhibitor PX-12 (1-methylpropyl 2-imidazolyl disulfide) decreases thioredoxin-1 and VEGF levels in cancer patient plasma. / Baker, Amanda F; Dragovich, Tomislav; Tate, Wendy R.; Ramanathan, Ramesh K.; Roe, Denise; Hsu, Chiu-Hsieh; Kirkpatrick, D. Lynn; Powis, Garth.

In: The Journal of Laboratory and Clinical Medicine, Vol. 147, No. 2, 02.2006, p. 83-90.

Research output: Contribution to journalArticle

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