Cooperative antitumor effect of multitargeted kinase inhibitor ZD6474 and ionizing radiation in glioblastoma.
OBJECTIVE
Glioblastoma multiforme is an aggressive disease in which vascular endothelial growth factor (VEGF) and the EGF receptor (EGFR) are implicated in tumor growth, relapse, and resistance to radiotherapy and chemotherapy. The VEGF receptors VEGFR-1 (flt-1) and VEGFR-2 (KDR), typically present on endothelial cells, have also been identified in human glioblastoma tissues and cell lines. In addition, EGFR is dysregulated in the majority of human glioblastomas and EGFR overexpression correlates with shorter survival. We have investigated the antitumor and antiangiogenic effect of ZD6474, an inhibitor of both VEGFR and EGFR signaling as a single agent and in combination with ionizing radiation.


METHODS
We have used ZD6474 and/or ionizing radiation in human glioblastoma cell lines D54 and U251 in vitro and in nude mice bearing established xenografts. The effects of treatment on tumor blood vessels and protein expression were evaluated by Western blot and immunohistochemistry.


RESULTS
As single agents, ionizing radiation and ZD6474 caused a dose-dependent inhibition of soft agar growth in D54 and U251 cell lines, whereas a cooperative effect was obtained in combination. Treatment of mice bearing D54 xenografts with either ZD6474 or radiotherapy alone caused tumor growth inhibition that was reversible upon treatment cessation. A cooperative and long-lasting inhibition of tumor growth was obtained with ZD6474 in combination with concomitant radiotherapy. The antiproliferative effect was accompanied by inhibition of VEGF protein expression and inhibition of angiogenesis as measured by vessel counting.


CONCLUSIONS
This study shows the antitumor activity of ZD6474 in combination with ionizing radiation in glioblastoma both in vitro and in vivo, and provides a scientific rationale to evaluate ZD6474 alone or in combination with radiotherapy in patients affected by this disease.
Damiano
Vincenzo
V
Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università di Napoli Federico II, Italy.
Melisi
Davide
D
Bianco
Cataldo
C
Raben
David
D
Caputo
Rosa
R
Fontanini
Gabriella
G
Bianco
Roberto
R
Ryan
Anderson
A
Bianco
A Raffaele
AR
De Placido
Sabino
S
Ciardiello
Fortunato
F
Tortora
Giampaolo
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003094:Collagen / Q000494:pharmacology; D003131:Combined Modality Therapy / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000532:radiotherapy*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007797:Laminin / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010880:Piperidines / Q000494:pharmacology*; D011509:Proteoglycans / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D011839:Radiation, Ionizing; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000970:Antineoplastic Agents; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007797:Laminin; D010880:Piperidines; D011509:Proteoglycans; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; C452423:vandetanib