Modulation of intratumoral hypoxia by the epidermal growth factor receptor inhibitor gefitinib detected using small animal PET imaging.
Blockade of signaling through the epidermal growth factor receptor (EGFR) tyrosine kinase by inhibitors such as gefitinib (Iressa) can inhibit tumor angiogenesis and enhance responses to ionizing radiation. In this study, the ability of gefitinib to modulate intratumoral oxygenation was evaluated in human EGFR-expressing A431 squamous cell carcinoma xenografts using in vivo small animal positron emission tomography (PET) imaging with the hypoxia marker [(18)F]fluoroazomycin arabinoside (FAZA) and by the immunohistochemical detection of hypoxia-induced adducts of the 2-nitroimidazole, pimonidazole. Serial noninvasive PET imaging of A431 xenografts showed a significant reduction in FAZA uptake following treatment with 75 mg/kg/d of gefitinib [tumor to background ratio, 6.1 +/- 1.0 (pretreatment) versus 2.3 +/- 0.6 (posttreatment); P = 0.0004]. Similarly, ex vivo quantitation of FAZA uptake showed significantly reduced FAZA uptake in established A431 xenografts treated with gefitinib compared with vehicle control (tumor to blood ratio for controls versus gefitinib, 8.0 +/- 3.0 versus 2.7 +/- 0.8; P = 0.007; or tumor to muscle ratio controls versus gefitinib, 8.6 +/- 2.8 versus 2.6 +/- 1.0; P = 0.002). The effect of gefitinib treatment seemed to be independent of tumor size. In addition, gefitinib treatment reduced pimonidazole-binding in A431 xenografts measured after 5 and 8 days of gefitinib treatment compared with baseline and with tumors treated with vehicle alone. A strong correlation was observed between pimonidazole binding and FAZA uptake. Together, these findings show that gefitinib reduces intratumoral hypoxia.
Solomon
Benjamin
B
Research Division, Peter MacCallum Cancer Institute, Melbourne, Australia.
Binns
David
D
Roselt
Peter
P
Weibe
Leonard I
LI
McArthur
Grant A
GA
Cullinane
Carleen
C
Hicks
Rodney J
RJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging* / Q000209:etiology / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D000077156:Gefitinib; D006801:Humans; D000860:Hypoxia / Q000000981:diagnostic imaging* / Q000209:etiology / Q000378:metabolism; D008175:Lung Neoplasms / Q000000981:diagnostic imaging* / Q000209:etiology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009593:Nitroimidazoles / Q000493:pharmacokinetics; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D049268:Positron-Emission Tomography; D011799:Quinazolines / Q000494:pharmacology*; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D005462:Fluorine Radioisotopes; D009593:Nitroimidazoles; D011799:Quinazolines; C498052:fluoroazomycin arabinoside; D066246:ErbB Receptors; D000077156:Gefitinib; D010100:Oxygen