Normal tissues toxicities triggered by combined anti-angiogenic and radiation therapies: hurdles might be ahead.
BACKGROUND
Combined-modality therapy is a promising approach to improve the therapeutic index of radiotherapy. However, these improvements could come at the cost of increased toxicities. Clinical trials evaluating anti-tumour efficacy of bevacizumab combined with radiotherapy have encountered unexpected side effects. This study is the first systematic evaluation of normal tissue toxicity triggered by anti-angiogenic agents combined with radiation therapy in mice.


METHODS
Effect of a mouse anti-VEGF antibody was monitored on acute toxicity studying radiation-induced intestinal ulceration (12 Gy TBI); on subacute toxicity using a model of oral mucositis (16.5 Gy); on late radiation injuries by monitoring lung fibrosis (bleomycin and 19 Gy).


RESULTS
Combination of irradiation with anti-VEGF antibody enhanced intestinal damages with severe epithelial ulcerations, had no adverse impact on oral mucositis and dramatically worsened the fibrotic picture induced by bleomycin and irradiation to the lung.


CONCLUSIONS
These reports bring to light the important questions about safety and underscore the need for appropriate preclinical modelling of the impact on normal tissues of novel drug-radiation regimens. Our findings also highlight the complexity of anti-VEGF action, which could in defined conditions exert tissue-specific protection. The findings indicate that the combination of targeted drugs with radiotherapy should be approached with caution.
Unité Mixte de Recherche radiothérapie moléculaire. INSERM Unité 1030, Institut Gustave Roussy, PR1, 114, Rue E Vaillant, LabEx Lermit, 94805 Villejuif CEDEX, France.
M
M
Mangoni
M-C
MC
Vozenin
G
G
Biti
E
E
Deutsch
D020533:Angiogenesis Inhibitors / Q000633:toxicity*; D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D003131:Combined Modality Therapy / Q000009:adverse effects / Q000379:methods; D005260:Female; D005355:Fibrosis / Q000209:etiology; D007422:Intestines / Q000528:radiation effects; D008168:Lung / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009061:Mouth Mucosa / Q000473:pathology / Q000528:radiation effects; D011833:Radiation Injuries, Experimental / Q000209:etiology*; D011878:Radiotherapy / Q000009:adverse effects*; D011879:Radiotherapy Dosage; D013280:Stomatitis / Q000209:etiology
D020533:Angiogenesis Inhibitors; D001761:Bleomycin