Combined effect of gefitinib ('Iressa', ZD1839) and targeted radiotherapy with 211At-EGF.
The EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor) gefitinib ['Iressa' (trademark of the AstraZeneca group of companies), ZD1839] increases the cellular uptake of radiolabelled epidermal growth factor (EGF). We investigated gefitinib treatment combined with astatine-211 EGF targeting in vitro using two cell lines expressing high levels of EGFR: A431 (sensitive to gefitinib) and U343MGaCl2:1 (resistant to gefitinib). In both cell lines, the uptake of 211At-EGF was markedly increased by concomitant treatment with gefitinib. Survival was investigated using both a clonogenic survival assay and a cell growth assay. Combined gefitinib and 211At-EGF treatment reduced the survival of U343 cells 3.5-fold compared with 211At-EGF alone. In A431 cells, 211At-EGF treatment resulted in very low survival, but combined treatment with gefitinib increased the survival by about 20-fold. These results indicate that combined treatment with gefitinib might increase the effect of ligand-mediated radionuclide therapy in gefitinib-resistant tumours and decrease the effect of such therapy in gefitinib-sensitive tumours.
Sundberg
Asa Liljegren
AL
Division of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden. Asa.Liljegren@bms.uu.se
Almqvist
Ylva
Y
Orlova
Anna
A
Blomquist
Erik
E
Jensen
Holger J
HJ
Gedda
Lars
L
Tolmachev
Vladimir
V
Carlsson
Jörgen
J
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001246:Astatine / Q000627:therapeutic use*; D001254:Astrocytoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy / Q000379:methods; D004815:Epidermal Growth Factor / Q000627:therapeutic use*; D000077156:Gefitinib; D006801:Humans; D011799:Quinazolines / Q000627:therapeutic use*; D019275:Radiopharmaceuticals / Q000627:therapeutic use; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D011799:Quinazolines; D019275:Radiopharmaceuticals; D004815:Epidermal Growth Factor; D000077156:Gefitinib; D001246:Astatine