ABSTRACT
OBJECTIVE: The goal of this study was to develop a 99mTc labelled human epidermal growth factor (hEGF) for the in-vivo prediction of cancer cell response to farnesyltransferase inhibitor (FTI) therapy. This is based on the observation that internalization of EGF receptors is inhibited by FTIs. METHODS: We describe the radiolabelling of 99mTc-hEGF using the hydrazinonicotinamide (HYNIC) linker. Binding characteristics of 99mTc-HYNIC-hEGF to the EGF receptor are explored using an in-vitro binding assay. Biodistribution data of the compound in mice and tumour uptake in LoVo tumour bearing athymic mice before and after farnesyltransferase inhibitor therapy are presented. RESULTS: No colloid formation was observed. Binding parameters and LoVo tumour uptake of 99mTc-HYNIC-hEGF did not differ significantly from directly labelled 123I-hEGF values. However, the biodistribution data of the 99mTc-HYNIC-hEGF showed higher uptake in liver and intestines and decreased stomach uptake compared to its 123I analogue. Eight hours after farnesyltransferase inhibitor therapy with R115777, LoVo tumour uptake of 99mTc-HYNIC-hEGF decreased significantly, as shown using planar gamma scintigraphy (the ratio tumour vs. thigh dropped from 2.54+/-0.83 to 0.99+/-0.18). These data confirm the results obtained using 123I-hEGF. CONCLUSION: These data suggest that 99mTc-HYNIC-hEGF is a promising and selective new radiotracer for in-vivo monitoring of the EGF receptor with SPECT. Moreover, 99mTc-HYNIC-hEGF is a possible tool for early therapy response prediction of farnesyltransferase inhibitors.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Colonic Neoplasms/drug therapy , Colonic Neoplasms/metabolism , Epidermal Growth Factor/pharmacokinetics , ErbB Receptors/metabolism , Organotechnetium Compounds/pharmacokinetics , Quinolones/administration & dosage , Animals , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Colonic Neoplasms/diagnostic imaging , Epidermal Growth Factor/chemistry , Farnesyltranstransferase , Humans , Male , Metabolic Clearance Rate , Mice , Organ Specificity , Organotechnetium Compounds/chemistry , Radionuclide Imaging , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacokinetics , Tissue Distribution , Treatment OutcomeABSTRACT
BACKGROUND: Ageing is associated with a progressive loss of renal mass and kidney length and a decline in glomerular filtration rate (GFR). This study evaluated a possible correlation between renal function and kidney size measured by ultrasonography (US), and whether the latter helps estimate GFR in the elderly. METHODS: Twenty-five medically stable elderly patients (mean age 85 +/- 5 yrs) were examined in a geriatric ward at a university hospital. Blood samples were taken to determine serum creatinine (Cr) levels. On the same day, 51chromium ethylenediamine tetraacetic acid (51Cr-EDTA) clearance was performed as the gold standard of GFR. US measured kidney length, transverse and anteroposterior dimensions. RESULTS: Serum Cr (r=-0.67; p=0.0002), Cockcroft-Gault formula (r=0.82; p<0.0001), absolute length (r=0.51; p=0.008) and volume kidney (r=0.46; p=0.02) correlated significantly with GFR. After receiver operating curve (ROC) analysis, length was less specific than sensitive in detecting renal impairment. Adding length to the Cockcroft-Gault formula did not improve GFR estimation (p=0.44). In contrast, adding length to serum Cr levels improved GFR estimation (p=0.015). CONCLUSION: In the elderly, kidney length and volume significantly correlated with GFR. However, length has a low specificity in predicting renal impairment. Therefore, in clinical practice, serum Cr levels and calculated Cr clearance are more useful in predicting renal impairment. However, normal kidney length can help to exclude renal impairment in the elderly at risk of GFR underestimation by a calculated Cr clearance.
