Synthesis, biodistribution and effects of farnesyltransferase inhibitor therapy on tumour uptake in mice of 99mTc labelled epidermal growth factor.
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.


CONCLUSIONS
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.
Cornelissen
Bart
B
Laboratory for Radiopharmacy, Gent University, Belgium. bart.cornelissen@utoronto.ca
Kersemans
Veerle
V
Burvenich
Ingrid
I
Oltenfreiter
Ruth
R
Vanderheyden
Jean-Luc
JL
Boerman
Otto
O
Vandewiele
Christophe
C
Slegers
Guido
G
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000737:chemistry / Q000493:pharmacokinetics*; D066246:ErbB Receptors / Q000378:metabolism*; D051231:Farnesyltranstransferase; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D009928:Organ Specificity; D015609:Organotechnetium Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D015363:Quinolones / Q000008:administration & dosage*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014018:Tissue Distribution; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D015609:Organotechnetium Compounds; D015363:Quinolones; D019275:Radiopharmaceuticals; C502075:technetium 99m HYNIC-human epidermal growth factor; D004815:Epidermal Growth Factor; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D066246:ErbB Receptors; C402769:tipifarnib