Metabolite changes in HT-29 xenograft tumors following HIF-1α inhibition with PX-478 as studied by MR spectroscopy in vivo and ex vivo
Metabolite changes in HT-29 xenograft tumors following HIF-1α inhibition with PX-478 as studied by MR spectroscopy in vivo and ex vivo
复制标题
DOI：
10.1002/nbm.977
复制
发表时间：
2005-11-01
影响因子：
2.9
通讯作者：
Gillies, RJ
中科院分区：
文献类型：
--
作者：
Jordan, NF;Black, K;Gillies, RJ
缺氧诱导转录因子（HIF-1 α）在肿瘤发展中起着核心作用。PX-478是一种实验性抗癌药物，已知可抑制实验性肿瘤中的HIF-1 α。本研究的目的是在I/II期临床试验之前确定mrs可见的PX-478代谢生物标志物。在单剂量PX-478治疗前和24小时后，从HT-29肿瘤异种移植物中获得了单体素体内定位h -1光谱。水溶性和亲脂性代谢物的谱图也用H-1和P-31光谱进行了体外峰鉴定，并询问了反应的潜在生物化学原理。在PX-478治疗12和24小时后，体内总胆碱（tCho）共振显著降低，这一点通过高分辨率1h和P-31 mrs得到证实。在非水提取物中，心磷脂、PtdEtn（磷脂酰乙醇胺）和PtdI（磷脂酰肌醇）显著降低。尽管体内和体外乳酸（和脂质）共振有降低的趋势，但这些变化并不显著。这与PX-478在HT-29细胞中对体外葡萄糖消耗和乳酸生成的抑制形成对比。tCho的显著而强劲的变化已将其确定为体内药物反应的潜在1H mrs可见生物标志物，而高分辨率光谱表明GPC， PC, myol， PE， GPE， CL， PtdEtn和Ptdl是潜在的体外反应生物标志物。版权所有(c) 2005 John Wiley & Sons, Ltd。
The hypoxia-inducible transcription factor (HIF-1 alpha) plays a central role in tumor development. PX-478 is an experimental anti-cancer drug known to inhibit HIF-1 alpha in experimental tumors. The purpose of this study was to identify MRS-visible metabolic biomarkers for PX-478 response prior to phase I/II clinical trials. Single-voxel in vivo localized H-1 spectra were obtained from HT-29 tumor xenografts prior and up to 24 h after treatment with a single dose of PX-478. Profiles of water-soluble and lipophilic metabolites were also examined ex vivo with both H-1 and P-31 spectroscopy for peak identification and to interrogate the underlying biochemistry of the response. The total choline (tCho) resonance was significantly decreased in vivo 12 and 24 h following treatment with PX-478 and this was confirmed with high-resolution 1 H and P-31 MRS. In non-aqueous extracts, significant reductions in cardiolipin, PtdEtn (phosphatidylethanolamine) and PtdI (phosphatidylinositol) were seen in response to PX-478. Although there were trends to a decrease in lactate (and lipid) resonances in vivo and ex vivo, these changes were not significant. This is in contrast to inhibition of in vitro glucose consumption and lactate production by PX-478 in HT-29 cells. The significant and robust change in tCho has identified this as a potential 1H MRS-visible biomarker for drug response in vivo while high-resolution spectroscopy indicated that GPC, PC, myol, PE, GPE, CL, PtdEtn and Ptdl are potential ex vivo response biomarkers. Copyright (c) 2005 John Wiley & Sons, Ltd.