Effects of the VEGFR inhibitor ZD6474 in combination with radiotherapy and temozolomide in an orthotopic glioma model.
OBJECTIVE
The extensive neovascularisation of malignant glioma is mainly influenced by vascular endothelial growth factor (VEGF). The effect of ZD6474, a potent inhibitor of VEGF-receptor-2, was evaluated in combination with either radiotherapy or temozolomide.


METHODS
The effects on glioma growth were investigated in the intracerebral BT4C rat glioma model. ZD6474 30 mg/kg was given alone or in combination with radiotherapy 12 Gy x 1 or with temozolomide 100 mg/kg for 3 days. Two different experiments were performed comparing ZD6474 to radiotherapy or temozolomide. For each experiment 28 animals were randomized into four groups.


RESULTS
ZD6474 in combination with radiotherapy significantly decreased tumour area by 66% compared with controls whereas the combination with temozolomide decreased tumour area by 74%.


CONCLUSIONS
ZD6474 in combination with two standard modalities in the treatment of malignant glioma, radiotherapy and chemotherapy, markedly decreased the growth of an intracerebral experimental glioma. These results justify further investigations of these therapies in combination.
Sandström
Maria
M
Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden. maria.sandstrom@onkologi.umu.se
Johansson
Mikael
M
Bergström
Per
P
Bergenheim
A Tommy
AT
Henriksson
Roger
R
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D066246:ErbB Receptors / Q000187:drug effects / Q000235:genetics; D005910:Glioma / Q000473:pathology / Q000628:therapy*; D009368:Neoplasm Transplantation; D010880:Piperidines / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D051381:Rats; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D010880:Piperidines; D011799:Quinazolines; D003606:Dacarbazine; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; D000077204:Temozolomide; C452423:vandetanib