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

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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 et al. J Lab Clin Med. 2006 Feb.

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.

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Figures

Figure 1

Figure 1

Trx-1 in mouse and human plasma. A. Recombinant mouse Trx-1 added to mouse plasma (gray line) increased the endogenous peak (black line) at 11.68 kDa corresponding to the predicted molecular weight of mouse Trx-1. B. Recombinant purified human Trx-1 added to normal human plasma (gray line) increased the endogenous human Trx-1 peak (black line) at 11.73 kDa. C. Overlay of the spectra showing depletion of the 11.73 kDa peak after immunodepletion. Arrows reflect the volume of anti-Trx-1 bound beads used to remove Trx-1 protein from plasma.

Figure 2

Figure 2

PX-12 decreases Trx-1 in mouse plasma. Each point represents the mean ± S.E. of four non-tumor bearing mice injected with 25mg/kg PX-12.

Figure 3

Figure 3

Plasma Trx-1 levels in healthy volunteers and cancer patients. Samples from 7 normal subjects and 31 cancer patients from a Phase I study of PX-12. Plasma was collected before treatment with PX-12. Pretreatment compared to normal controls (p<0.001). The graph shows: mean, 25 and 75 percentiles (gray box), 10 and 90 percentiles (whiskers).

Figure 4

Figure 4

Decrease in patient plasma Trx-1 and VEGF after PX-12 administration. The change in plasma Trx-1 or VEGF 4 hr after PX-12 administration compared to the pretreatment level in the same patient, plotted against the pretreatment level. The relationship between preand post-PX-12 treatment Trx-1 levels was assessed using a linear regression model with a square root transformation of the dependent variable. A. Plasma Trx-1. The line is the correlation (R2 = 0.225), n = 31, p = 0.007. B. Plasma VEGF. The line is the correlation (R2 = 0.465), n = 19, p = 0.001.

Figure 5

Figure 5

Representative SELDI-TOF spectra from plasma of one patient pre-PX-12 administration (solid line) compared to plasma 4 hrs post-PX-12 treatment (dashed line).

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References

    1. Gromer S, Urig S, Becker K. The thioredoxin system--from science to clinic. Med Res Rev. 2004;24(1):40–89. - PubMed
    1. Arner ES, Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem. 2000;267(20):6102–6109. - PubMed
    1. Powis G, Montfort WR. Properties and biological activities of thioredoxins. Annu Rev Pharmacol Tox. 2001;41:261–295. - PubMed
    1. Fujii J, Ikeda Y. Advances in our understanding of peroxiredoxin, a multifunctional, mammalian redox protein. Redox Rep. 2002;7(3):123–130. - PubMed
    1. Mitomo K, Nakayama K, Fujimoto K, Sun X, Seki S, Yamamoto K. Two different cellular redox systems regulate the DNA-binding activity of the p50 subunit of NF-kappa B in vitro. Gene. 1994;145(2):197–203. - PubMed

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