Abstract
1168
Objectives To determine whether treatment with bevacizumab causes changes in the expression of αvβ3 integrins that can be measured by PET with 68Ga-NODAGA-c(RGDfK).
Methods Nude mice bearing A431 squamous cell carcinoma xenografts were treated with 20 mg/kg bevacizumab or vehicle for up to three weeks. The uptake of 68Ga-NODAGA-c(RGDfK) was measured in control and treated tumors using small animal PET/CT and expressed as percent injected activity per gram (%IA/g). Frozen sections from control and treated tumors were stained with antibodies against CD31 (blood vessel marker); human αvβ3 integrin and mouse β3 integrin. Blood vessels were counted in four high power fields.
Results Bevacizumab significantly inhibited the growth of A431 tumors during the first two weeks of treatment, after that tumors started to regrow. Microvascular density in bevacizumab treated tumors at day 7 and 14 was at least 2 times less compared to control tumors. Blood vessels were also less dilated and irregularly configured than in control tumors. 68Ga-NODAGA-c(RGDfK) uptake in bevacizumab treated tumors at day 7 was increased by 36% (from 1.10 ± 0.14 %IA/g to 1.50 ± 0.16 %IA/g, p <0.01) compared to the same tumors before treatment and by 54 % (from 0.97 ± 0.31 %IA/g to 1.50 ± 0.16 %IA/g, p <0.01) compared to control tumors. At day 14 68Ga-NODAGA-c(RGDfK) uptake in bevacizumab treated tumors decreased to the pretreatment levels. Tumor cells in A431 xenografts were negative for αvβ3 integrin expression and blood vessels in control and treated tumors expressed mouse β3 integrin.
Conclusions Inhibiting tumor angiogenesis and growth with bevacizumab resulted in an increase in 68Ga-NODAGA-c(RGDfK) uptake by A431 tumors. This increase correlated with reduced vessel density and normalization of tumor vessel morphology. If confirmed in other tumor models, PET imaging with Ga68-NODAGA-c(RGDfK) could potentially be used to monitor non-invasively the effects of bevacizumab on the tumor microvasculature.
Research Support German Research Foundation (DFG- SFB 850 Z2 to WAW; DFG SFB850 Z1 to MW, SL; BMBF DKTK)