Noninvasive magnetic resonance spectroscopic pharmacodynamic markers of the choline kinase inhibitor MN58b in human carcinoma models
Noninvasive magnetic resonance spectroscopic pharmacodynamic markers of the choline kinase inhibitor MN58b in human carcinoma models
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DOI：
10.1158/0008-5472.can-05-1338
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发表时间：
2006-01-01
期刊：
影响因子：
11.2
通讯作者：
Chung, YL
中科院分区：
文献类型：
--
作者：
Al-Saffar, NMS;Troy, H;Chung, YL
MN58b是一种抑制胆碱激酶的新型抗癌药物，可抑制磷脂胆碱的合成。这项工作的目的是开发一种非侵入性和强大的药效学生物标志物，用于靶向抑制和潜在的MN58b治疗后的肿瘤反应。用质子（111）和磷（P-31）磁共振波谱（MRS）检测人HT29（结肠癌）和MDA-MB-231（乳腺癌）癌细胞在MN58b培养和异种移植前后的变化。我们还在MDA-MB-231细胞中进行了MN58b处理的体外时间过程研究。此外，还进行了细胞胆碱激酶活性的酶促测定。MN58b处理后，两种细胞系的体外总胆碱和磷胆碱水平均下降（P < 0.05），而无活性类似物ACG20b则没有影响。在MDA-MB-231细胞中，早在MN58h后4小时，磷酸胆碱就显著下降，而在48小时时，细胞数量下降。在MN58b治疗后，磷酸胆碱水平（MRS测量）与胆碱激酶活性之间也存在显著相关性（r(2) = 0.95, p = 0.0008）。在HT29和MDA-MB-231异种移植物中，磷酸单酯也显著降低（P < 0.05），而对照组无显著变化。肿瘤提取物的P-31- mrs和H-1-MRS均显著降低了磷脂胆碱(P
MN58b is a novel anticancer drug that inhibits choline kinase, resulting in inhibition of phosphocholine synthesis. The aim of this work was to develop a noninvasive and robust pharmacodynamic biomarker for target inhibition and, potentially, tumor response following MN58b treatment. Human HT29 (colon) and MDA-MB-231 (breast) carcinoma cells were examined by proton (111) and phosphorus (P-31) magnetic resonance spectroscopy (MRS) before and after treatment with MN58b both in culture and in xenografts. An in vitro time course study of MN58b treatment was also carried out in MDA-MB-231 cells. In addition, enzymatic assays of choline kinase activity in cells were done. A decrease in phosphocholine and total choline levels (P < 0.05) was observed in vitro in both cell lines after MN58b treatment, whereas the inactive analogue ACG20b had no effect. In MDA-MB-231 cells, phosphocholine fell significantly as early as 4 hours following MN58h treatment, whereas a drop in cell number was observed at 48 hours. Significant correlation was also found between phosphocholine levels (measured by MRS) and choline kinase activities (r(2) = 0.95, p = 0.0008) following MN58b treatment. Phosphomonoesters also decreased significantly (P < 0.05) in both HT29 and MDA-MB-231 xenografts with no significant changes in controls. P-31-MRS and H-1-MRS of tumor extracts showed a significant decrease in phosphocholine (P