Ionizing radiation antagonizes tumor hypoxia induced by antiangiogenic treatment.
OBJECTIVE
The combined treatment modality of ionizing radiation with inhibitors of angiogenesis is effective despite the supposition that inhibition of angiogenesis might increase tumor hypoxia and thereby negatively affect radiation sensitivity. To directly assess this still controversial issue, we analyzed treatment-dependent alterations of tumor oxygenation in response to inhibition of angiogenesis alone, ionizing radiation, and combined treatment.


METHODS
Serial measurements with high-resolution [18F]fluoromisonidazole positron emission tomography and immunohistochemical detection of the endogenous hypoxia marker glucose transporter-1 were done to determine tumor hypoxia in a murine mammary carcinoma allograft model.


RESULTS
Inhibition of angiogenesis with the clinically relevant vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 reduced microvessel density but had only minimal effects on tumor growth, tumor cell apoptosis, and proliferation. However, PTK787/ZK222584 treatment increased overall and local tumor hypoxia as revealed by extended expression of the hypoxia marker glucose transporter-1 and increased uptake of [18F]fluoromisonidazole. Fractionated irradiation induced a strong growth delay, which was associated with enhanced apoptosis and reduced proliferation of tumor cells but only minor effects on microvessel density and allograft oxygenation. Combined treatment with fractionated irradiation resulted in extended tumor growth delay and tumor cell apoptosis but no increase in tumor hypoxia.


CONCLUSIONS
These results show that irradiation antagonizes the increase of hypoxia by vascular endothelial growth factor receptor tyrosine kinase inhibition and abrogates the potential negative effect on tumor hypoxia. Thus, the risk of treatment-induced hypoxia by inhibitors of angiogenesis exists but is kept minimal when combined with a cytotoxic treatment modality.
Riesterer
Oliver
O
Department of Radiation Oncology, University Hospital Zurich, Zürich, Switzerland.
Honer
Michael
M
Jochum
Wolfram
W
Oehler
Christoph
C
Ametamey
Simon
S
Pruschy
Martin
M
D000818:Animals; D002277:Carcinoma / Q000175:diagnosis / Q000532:radiotherapy*; D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D051272:Glucose Transporter Type 1 / Q000032:analysis / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D015674:Mammary Neoplasms, Animal / Q000175:diagnosis / Q000188:drug therapy / Q000532:radiotherapy*; D051379:Mice; D008920:Misonidazole / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000532:radiotherapy*; D010793:Phthalazines / Q000494:pharmacology; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000494:pharmacology; D014184:Transplantation, Homologous
D051272:Glucose Transporter Type 1; D010793:Phthalazines; D011725:Pyridines; C031843:fluoromisonidazole; C404768:vatalanib; D008920:Misonidazole