SU5416 and SU6668 attenuate the angiogenic effects of radiation-induced tumor cell growth factor production and amplify the direct anti-endothelial action of radiation in vitro.
In recent decades, radiation research has concentrated primarily on the cancer cell compartment. Much less is known about the effect of ionizing radiation on the endothelial cell compartment and the complex interaction between tumor cells and their microenvironment. Here we report that ionizing radiation is a potent antiangiogenic agent that inhibits endothelial cell survival, proliferation, tube formation and invasion. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor were able to reduce the radiosensitivity of endothelial cells. Yet, it is also found that radiation induces angiogenic factor production by tumor cells that can be abrogated by the addition of antiangiogenic agents. Receptor tyrosine kinase inhibitors of Flk-1/KDR/VEGFR2, FGFR1 and PDGFR beta, SU5416, and SU6668 enhanced the antiangiogenic effects of direct radiation of the endothelial cells. In a coculture system of PC3 prostate cancer cells and endothelial cells, isolated irradiation of the PC3 cells enhanced endothelial cell invasiveness through a Matrigel matrix, which was inhibited by SU5416 and SU6668. Furthermore, ionizing radiation up-regulated VEGF and basic fibroblast growth factor in PC3 cells and VEGFR2 in endothelial cells. Together these findings suggest a radiation-inducible protective role for tumor cells in the support of their associated vasculature that may be down-regulated by coadministration of angiogenesis inhibitors. These results rationalize concurrent administration of angiogenesis inhibitors and radiotherapy in cancer treatment.
Abdollahi
Amir
A
Department of Radiation Oncology, German Cancer Research Center and University of Heidelberg Medical School, 69120 Heidelberg, Germany.
Lipson
Kenneth E
KE
Han
Xiaohong
X
Krempien
Robert
R
Trinh
Thuy
T
Weber
Klaus J
KJ
Hahnfeldt
Philip
P
Hlatky
Lynn
L
Debus
Juergen
J
Howlett
Anthony R
AR
Huber
Peter E
PE
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects*; D002478:Cells, Cultured; D004307:Dose-Response Relationship, Radiation; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D007700:Kinetics; D008222:Lymphokines / Q000494:pharmacology; D008297:Male; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D000078183:Oxindoles; D010315:Particle Accelerators; D011422:Propionates; D011471:Prostatic Neoplasms / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured / Q000502:physiology / Q000528:radiation effects; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014965:X-Rays
D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D000078183:Oxindoles; D011422:Propionates; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; C116890:Semaxinib; C412603:orantinib