Targeting of glucose transport proteins for tumor imaging: is it feasible?

UNLABELLED: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Labeling cyclic glycoprotein IIb/IIIa receptor antagonists with 99mTc by the preformed chelate approach: effects of chelators on properties of [99mTc]chelator-peptide conjugates.

Several cyclic GPIIb/IIIa receptor antagonists were labeled with 99mTc by the preformed chelate approach using chelators such as H4L1 [4,5-bis(mercaptoacetamido)pentanoic acid], H4L2 [3,4-bis-(mercaptoacetamido)benzoic acid], H3L3 [2-(mercapto)ethylaminoacetyl-L-cysteine], H4L4 [N-(mercaptoacetyl)glycylglycylglycine], H4L5 [N-[2-(mercapto)propionyl]glycylglycylglycine], and H4L6 [N-[2-(mercapto)propionyl]glycylglycyl-gamma-aminobutyric acid]. In this approach, the [99mTc]chelator complexes are formed first, followed by the activation of the carboxylic group on the complex by formation of its tetrafluorophenol (TFP) ester and the conjugation of the TFP ester with an amino group of a cyclic GPIIb/IIIa receptor antagonist. The 99mTc-labeled cyclic GPIIb/IIIa receptor antagonists were characterized by radio-HPLC (high-performance liquid chromatography); differences in lipophilicity of the [99mTc]chelator-peptide conjugate are attributable to the effects of both the cyclic peptide and the chelator.