ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinase activity in combination with radiotherapy.
Radiation enhances both epithelial growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) expression, which are a part of key pathways for tumor progression. Some tumors may not respond well to EGFR inhibitors alone or may develop resistance to EGFR inhibitors. Therefore, drug therapy targeted to VEGF receptors and EGFRs, when combined with radiotherapy (RT), may improve tumor control and provide wider applicability. This article focuses on ZD6474, an inhibitor of EGFR and VEGF receptor signaling in combination with RT. We discuss preclinical and clinical studies with RT and inhibitors of VEGF or EGFR signaling first. We then address issues associated with ZD6474 pharmacokinetic dosing, and scheduling when combined with RT. We also discuss ZD6474 in the context of anti-EGFR therapy resistance. Dual inhibition of EGFR and VEGF receptor signaling pathways shows promise in enhancing RT efficacy.
Frederick
Barbara
B
Department of Radiation Oncology, University of Colorado Health Sciences Center, Aurora, CO 80010-0510, USA.
Gustafson
Dan
D
Bianco
Cataldo
C
Ciardiello
Fortunato
F
Dimery
Isaiah
I
Raben
David
D
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D003131:Combined Modality Therapy; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000532:radiotherapy*; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000378:metabolism / Q000532:radiotherapy*; D010880:Piperidines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011799:Quinazolines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000528:radiation effects; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D015854:Up-Regulation; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
D020533:Angiogenesis Inhibitors; D010880:Piperidines; D011799:Quinazolines; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; C452423:vandetanib