School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
Nucl Med Biol. 2011 Apr;38(3):339-46. doi: 10.1016/j.nucmedbio.2010.09.005. Epub 2010 Dec 3.
Changes in 2-[(18)F]-fluoro-2-deoxy-D-glucose (FDG) incorporation by tumors, detected using positron emission tomography, during response to chemotherapy are utilized clinically in patient management. Here, the effect of treatment with growth-inhibitory doses of the anti-human epidermal growth factor receptor-2 antibody trastuzumab (Herceptin) on the incorporation of FDG by breast tumor cells was measured along with hexokinase (HK) and glucose transport to determine the potential of FDG-positron emission tomography in predicting response to these biological anti-cancer therapies and their modulatory effects on the steps involved in FDG incorporation.
The sensitivity to trastuzumab of three breast tumor cell lines, SKBr3, MDA-MB-453 and MDA-MB-468, expressing human epidermal growth factor receptor-2 at high, medium and low levels, respectively, was determined using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay over a 6-day period, and a clonogenic assay was carried out after 7- and 10-day exposures. FDG incorporation by cells treated with growth-inhibitory doses of trastuzumab was carried out after 4 h and 2, 4 and 6 days of treatment. Glucose transport (rate of uptake of the non-metabolizable analogue [(3)H]O-methyl-D-glucose), HK activity and lactate production were measured on cells treated with inhibitory doses of trastuzumab for 6 days.
The IC(50) doses for SKBr3 and MDA-MB-453 and the IC(20) dose for MDA-MB-468 after 6 days of treatment with trastuzumab were 0.25, 1 and 170 μg/ml, respectively. FDG incorporation by SKBr3 and MDA-MB-453 cells was found to be decreased using IC(50) doses of trastuzumab for 6 days. At the IC(50) doses, FDG incorporation was also decreased at 4 days and, in the case of MDA-MB-453, even after 4 h of treatment. Decreased FDG incorporation corresponded with decreased HK activity in these cells. Lactate production, previously suggested to be a potential measure of response, was found to be significantly decreased by SKBr3 and MDA-MB-453 cells responding to trastuzumab.
FDG incorporation at the tumor cell level is modulated by treatment with growth-inhibitory doses of trastuzumab due to modulation of HK activity. Changes in lactate production may also be a useful determinant of response to trastuzumab.
使用正电子发射断层扫描（PET）检测到肿瘤中 2-[(18)F]-氟-2-脱氧-D-葡萄糖（FDG）的摄取变化，在化疗反应中被临床用于患者管理。在这里，我们测量了生长抑制剂量的抗人表皮生长因子受体 2 抗体曲妥珠单抗（赫赛汀）治疗对乳腺癌细胞摄取 FDG 的影响，同时测量了己糖激酶（HK）和葡萄糖转运，以确定 FDG-PET 在预测这些生物抗癌疗法反应及其对 FDG 摄取相关步骤的调节作用方面的潜力。
使用 MTT[3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴盐]测定法，在 6 天的时间内，确定三种表达人表皮生长因子受体 2 的乳腺癌细胞系 SKBr3、MDA-MB-453 和 MDA-MB-468 对曲妥珠单抗的敏感性，高、中、低水平，并用克隆形成测定法在 7 天和 10 天暴露后进行。用生长抑制剂量的曲妥珠单抗处理细胞 4 小时后和处理 2、4 和 6 天后，进行 FDG 摄取。用曲妥珠单抗抑制剂量处理 6 天后，测量葡萄糖转运（非代谢类似物[(3)H]O-甲基-D-葡萄糖的摄取速率）、HK 活性和乳酸产生。
用曲妥珠单抗处理 6 天后，SKBr3 和 MDA-MB-453 的 IC50 剂量和 MDA-MB-468 的 IC20 剂量分别为 0.25、1 和 170μg/ml。发现 SKBr3 和 MDA-MB-453 细胞的 FDG 摄取在用曲妥珠单抗的 IC50 剂量处理 6 天后降低。在 IC50 剂量下，甚至在 4 小时的处理后，MDA-MB-453 细胞的 FDG 摄取也降低了。在这些细胞中，FDG 摄取的减少与 HK 活性的降低相对应。以前被认为是潜在反应指标的乳酸产生，在曲妥珠单抗反应的 SKBr3 和 MDA-MB-453 细胞中被发现显著降低。
由于 HK 活性的调节，用生长抑制剂量的曲妥珠单抗处理会调节肿瘤细胞水平的 FDG 摄取。乳酸产生的变化也可能是曲妥珠单抗反应的一个有用决定因素。
