McPhail Lesley D, McIntyre Dominick J O, Ludwig Christian, Kestell Philip, Griffiths John R, Kelland Lloyd R, Robinson Simon P
Division of Basic Medical Sciences, St. George's, University of London, London, UK.
Neoplasia. 2006 Mar;8(3):199-206. doi: 10.1593/neo.05739.
The dose-dependent effects of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on rat GH3 prolactinomas were investigated in vivo. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to assess tumor blood flow/permeability pretreatment and 24 hours posttreatment with 0, 100, 200, or 350 mg/kg DMXAA. DCE-MRI data were analyzed using K(trans) and the integrated area under the gadolinium time curve (IAUGC) as response biomarkers. High-performance liquid chromatography (HPLC) was used to determine the plasma concentration of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) following treatment to provide an index of increased vessel permeability and vascular damage. Finally, tumor necrosis was assessed by grading hematoxylin and eosin-stained sections cut from the same tumors investigated by MRI. Both tumor K(trans) and IAUGC were significantly reduced 24 hours posttreatment with 350 mg/kg DMXAA only, with no evidence of dose response. HPLC demonstrated a significant increase in plasma 5-HIAA 24 hours posttreatment with 200 and 350 mg/kg DMXAA. Histologic analysis revealed some evidence of tumor necrosis following treatment with 100 or 200 mg/kg DMXAA, reaching significance with 350 mg/kg DMXAA. The absence of any reduction in K(trans) or IAUGC following treatment with 200 mg/kg, despite a significant increase in 5-HIAA, raises concerns about the utility of established DCE-MRI biomarkers to assess tumor response to DMXAA.
在体内研究了5,6 - 二甲基黄嘌呤 - 4 - 乙酸（DMXAA）对大鼠GH3催乳素瘤的剂量依赖性效应。使用动态对比增强磁共振成像（DCE - MRI）评估肿瘤血流量/渗透性，分别在使用0、100、200或350 mg/kg DMXAA进行预处理以及处理后24小时进行评估。使用转运常数（K(trans)）和钆时间曲线下的积分面积（IAUGC）作为反应生物标志物来分析DCE - MRI数据。使用高效液相色谱（HPLC）测定处理后血清素代谢物5 - 羟吲哚乙酸（5 - HIAA）的血浆浓度，以提供血管通透性增加和血管损伤的指标。最后，通过对从经MRI研究的相同肿瘤切取的苏木精和伊红染色切片进行分级来评估肿瘤坏死情况。仅在使用350 mg/kg DMXAA处理后24小时，肿瘤的K(trans)和IAUGC均显著降低，且无剂量反应的证据。HPLC显示，在使用200和350 mg/kg DMXAA处理后24小时，血浆5 - HIAA显著增加。组织学分析显示，在使用100或200 mg/kg DMXAA处理后有一些肿瘤坏死的证据，在使用350 mg/kg DMXAA处理时达到显著水平。尽管5 - HIAA显著增加，但在使用200 mg/kg处理后K(trans)或IAUGC没有任何降低，这引发了对既定的DCE - MRI生物标志物评估肿瘤对DMXAA反应效用的担忧。
