Baker Amanda F, Dragovich Tomislav, Tate Wendy R, Ramanathan Ramesh K, Roe Denise, Hsu Chiu-Hsieh, Kirkpatrick D Lynn, Powis Garth
Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA.
J Lab Clin Med. 2006 Feb;147(2):83-90. doi: 10.1016/j.lab.2005.09.001.
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.
硫氧还蛋白-1（Trx-1）是一种小型氧化还原蛋白，在许多人类肿瘤中过度表达，与肿瘤的侵袭性生长及患者生存率降低相关。Trx-1由肿瘤细胞分泌，在癌症患者血浆中的水平升高。PX-12是Trx-1的不可逆抑制剂，目前正作为一种抗肿瘤药物进行临床开发。在一项I期研究中，我们使用表面增强激光解吸电离飞行时间质谱（SELDI-TOF）来测量接受PX-12治疗患者的血浆Trx-1。癌症患者治疗前血浆Trx-1的平均水平显著升高，为182.0 ng/mL，而健康志愿者血浆中的水平为27.1 ng/mL。PX-12治疗显著降低了治疗前血浆Trx-1水平最高的癌症患者的血浆Trx-1。血浆血管内皮生长因子（VEGF）水平高与患者生存率降低相关。PX-12治疗还显著降低了治疗前VEGF水平高的癌症患者的血浆VEGF水平。SELDI-TOF质谱鉴定出另外七种血浆蛋白，其水平在给予PX-12后下降，其中一种被鉴定为截短形式的转甲状腺素蛋白。这项研究的结果表明，降低癌症患者血浆中升高的Trx-1水平可能是PX-12抑制肿瘤Trx-1的替代指标。此外，PX-12降低血浆VEGF水平，这可能有助于PX-12的抗肿瘤活性。
