Nelson C A, Wang Q J, Bourque J P, Crane P D
DuPont Merck Pharmaceutical Company, North Billerica, Massachusetts, USA.
J Nucl Med. 1996 Jun;37(6):1031-7.
If glucose transport proteins (Glut) are elevated in tumors they may be good targets for tumor imaging. For targeting, the overexpression of Glut should be a general characteristic of tumors. Moreover agents which bind to Glut should accumulate selectively in tumors.
To test this, we quantitated Glut in isolated membranes from three human tumor xenografts, two murine tumor models and normal murine tissues using direct binding studies. Additionally, the biodistribution of two compounds which bind to Glut, 7-[[(2-(3-(125I-p-hydroxyphenyl)propionyl)aminoethyl)amino]carbonyl]-7-+ ++desacetyl-forskolin([125I]HPP forskolin) and [3H]cytochalasin B, were studied in a tumor model which overexpressed Glut.
There were multiple classes of binding sites for [3H]cytochalasin B and a percentage of these sites were competitive with D-glucose but not L-glucose. The rank potency and IC50 values for [3H]cytochalasin B binding were: 2-deoxy-D-glucose (4.5 mM) > or = D-glucose (7 mM) > mannose (25 mM) > galactose (35 mM) > rhamnose (1-3 mM) > sorbitol (1-3 mM) and were similar to reported values for transport. The average density of Glut in four tumor models and normal tissues was between 0.7 and 4 pmole/mg protein, but Kd values were not significantly different (69 nM). In LX-1 human lung tumor xenograft (LX-1) Glut were 10-to-20-fold higher than other tissues (21.6 +/- 0.6 pmole/mg protein, p<0.01). Immunostaining of Glut-1 was more prominent in LX-1 than other xenograft tumors, consistent with the binding data. Glut density was highest in poorly vascularized regions suggesting that Glut upregulation was related to a biofeedback mediated event. Iodine-125 HPP-forskolin and [3H]cytochalasin B did not localize in LX-1 tumors.
Glut overexpression was not a common characteristic of the five tumors tested. Iodine-125 HPP-forskolin and [3H]cytochalasin B did not localize in LX-1 tumors, indicating that these agents did not target tumors with upregulated Glut. Results suggest that Glut are not a promising target for tumor imaging.
如果葡萄糖转运蛋白（Glut）在肿瘤中表达升高，它们可能是肿瘤成像的良好靶点。为了实现靶向，Glut的过表达应是肿瘤的一个普遍特征。此外，与Glut结合的试剂应在肿瘤中选择性积累。
为了验证这一点，我们使用直接结合研究对来自三种人肿瘤异种移植瘤、两种小鼠肿瘤模型和正常小鼠组织的分离膜中的Glut进行了定量。此外，在一个过表达Glut的肿瘤模型中研究了两种与Glut结合的化合物7-[[(2-(3-(125I-对羟基苯基)丙酰基)氨基乙基)氨基]羰基]-7-去乙酰基佛司可林（[125I]HPP佛司可林）和[3H]细胞松弛素B的生物分布。
[3H]细胞松弛素B有多种结合位点，其中一部分位点与D-葡萄糖竞争，但不与L-葡萄糖竞争。[3H]细胞松弛素B结合的效价顺序和IC50值为：2-脱氧-D-葡萄糖（4.5 mM）≥D-葡萄糖（7 mM）＞甘露糖（25 mM）＞半乳糖（35 mM）＞鼠李糖（1 - 3 mM）＞山梨醇（1 - 3 mM），与报道的转运值相似。四种肿瘤模型和正常组织中Glut的平均密度在0.7至4 pmol/mg蛋白之间，但解离常数（Kd）值无显著差异（69 nM）。在LX-1人肺肿瘤异种移植瘤（LX-1）中，Glut比其他组织高10至20倍（21.6±0.6 pmol/mg蛋白，p<0.01）。Glut-1的免疫染色在LX-1中比其他异种移植瘤更明显，与结合数据一致。Glut密度在血管化不良的区域最高，表明Glut上调与生物反馈介导的事件有关。碘-125 HPP-佛司可林和[3H]细胞松弛素B未在LX-1肿瘤中定位。
Glut过表达不是所测试的五种肿瘤的共同特征。碘-125 HPP-佛司可林和[3H]细胞松弛素B未在LX-1肿瘤中定位，表明这些试剂不能靶向Glut上调的肿瘤。结果表明，Glut不是肿瘤成像的有前景的靶点。
