Abstract
1706
Objectives Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) ZD1839 (Gefitinib, Iressa) has been approved for cancer treatment. We investigated whether ZD1839 treatment can mediate the in vivo tumor uptake enhancement of human EGF (hEGF), thereby increasing the potential of hEGF as a vehicle for EGFR-targeted imaging and possible therapy.
Methods Western blot was conducted to detect the effect of ZD1839 on EGFR signaling. Different EGFR-expressing tumor cells (SCC-1, 22B, A549, and HT-29) were pretreated with ZD1839, followed by addition of 125I-hEGF or 125I-Vectibix (an anti-EGFR mAb). Cell-associated activity was then measured. Nude mice bearing 22B or SCC-1 tumor xenografts were pretreated via i.p. injection of ZD1839 (50 mg/kg/day) or DMSO (vehicle control) for 4 days, followed by i.v. injection of 125I-EGF. Animals were then subjected to ex vivo biodistribution or small-animal SPECT/CT imaging, respectively.
Results The EGFR level was unchangeable whereas the phosphorylation status of EGFR was reduced in cells pretreated with ZD1839. ZD1839 mediated the formation of EGFR dimers, and cross-linking of 125I-EGF to ZD1839 treated cells revealed significantly increased receptor binding. In contrast, the binding of 125I-Vectibix to tumor cells was not increased. After ZD1839 pretreatment, the uptake of 125I-hEGF in SCC-1 tumor xenografts increased remarkably (from 3.83±1.15 to 11.25±4.45 %ID/g, p<0.001) at 4 h p.i., while the uptake of 125I-hEGF in normal organs was almost unchangeable. SPECT/CT images demonstrated significantly increased 22B tumor uptake of 125I-hEGF in ZD1839 pretreatment group.
Conclusions Although the total EGFR level was not increased, the binding of hEGF to EGFR-positive tumors enhanced significantly after ZD1839 treatment, which is likely due to the increased binding affinity of hEGF to EGFR dimers (induced by ZD1839). The detailed mechanism investigation is still in progress. However, this phenomenon suggests the potential of hEGF as a vehicle for EGFR-targeting when combines with EGFR TKI ZD1839