Dose scheduling of the dual VEGFR and EGFR tyrosine kinase inhibitor vandetanib (ZD6474, Zactima) in combination with radiotherapy in EGFR-positive and EGFR-null human head and neck tumor xenografts.
OBJECTIVE
Vandetanib (ZD6474, Zactima) is a novel, orally available inhibitor of vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase activity with additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. Vandetanib has demonstrated enhanced efficacy in combination with radiation therapy (RT) in human tumor models. This study aimed to evaluate the schedule-dependent interaction of clinically relevant dosing of vandetanib with RT in human head and neck cancer models that had been characterized as EGFR positive (EGFR+) or negative (EGFR-) in order to begin differentiating vandetanib and RT interactions at the level of antitumor (EGFR) or antivascular (VEGFR2) activities.


METHODS
The human head and neck squamous cell carcinoma (HNSCC) cell lines UMSCC2 (EGFR+) and UMSCC10 (EGFR(-)) are sensitive and resistant to EGFR inhibitors, respectively, while having similar sensitivity to ionizing radiation. Nude mice with UMSCC2 or UMSCC10 tumor xenografts were treated with vandetanib or RT alone, or with combinations of concomitant and sequential therapy. Vandetanib was dosed at 30 mg kg(-1) day(-1) based on pharmacokinetic studies in nude mice showing that this dose results in drug exposure similar to that seen in humans at clinical doses. RT was dosed at 3 Gy twice a week for two consecutive weeks for a total dose of 12 Gy.


RESULTS
Vandetanib alone caused regression in EGFR+ but not EGFR- tumors and RT therapy alone was similar in both tumor types. Combinations of vandetanib and RT showed concomitant use of vandetanib and RT was superior to RT followed by vandetanib or visa versa in EGFR- tumors. Therapeutic response of EGFR+ tumors was similar regardless of treatment sequencing.


CONCLUSIONS
The combination of vandetanib and RT is active in both EGFR+ and EGFR- HNSCC tumor xenografts, however, vandetanib alone is only active in EGFR+ xenografts. EGFR+ tumor response to vandetanib and RT was independent of treatment sequencing, but concomitant treatment was superior to sequencing in EGFR- tumors. These results suggest that the anti-VEGFR2 antitumor activity of vandetanib is enhanced by RT as presumably the activity seen in EGFR- tumors is due to antiangiogenic activity, whereas the anti-EGFR antitumor activity dominates in EGFR+ tumors such that RT enhancement is not observed.
Gustafson
Daniel L
DL
Department of Clinical Sciences, Animal Cancer Center, Room 208, Veterinary Teaching Hospital, Colorado State University, Fort Collins, CO 80523-1620, USA. Daniel.Gustafson@CololState.edu
Frederick
Barbara
B
Merz
Andrea L
AL
Raben
David
D
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000077156:Gefitinib; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D010880:Piperidines; D011799:Quinazolines; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077156:Gefitinib; C452423:vandetanib