155P - Effect of bevacizumab on tumour 5-fluorouracil concentration and microcirculatory parameters obtained by dynamic contrast-enhanced MRI in a hepatoce...
|Date||30 September 2012|
|Event||ESMO Congress 2012|
|Session||Poster presentation II|
|Topics|| Basic Science
S. Mikulski1, L. Wang2, S. Hartono3, L. Martarello4, T.S. Koh5, B.C. Goh2, C.H. Thng5, Q.S. Ng6
Vascular endothelial growth factor (VEGF) is expressed by tumours to promote angiogenesis. Clinical trials of anti-VEGF therapy combined with chemotherapy demonstrate improvement in survival. We investigate the effect of bevacizumab (bev), a humanized monoclonal antibody that inhibits VEGF-A, on tumour 5-fluorouracil (5FU) concentration in a hepatocellular carcinoma (HCC) xenograft model, together with changes in tumour microcirculatory parameters obtained by dynamic contrast-enhanced (DCE) MRI.Methods
48 immunodeficient mice implanted with subcutaneous HCC xenografts were first injected with bev (1mg/kg or 10mg/kg) or omalizumab (control). 1 day later, they received 5FU and were sacrificed. Tumour and plasma 5FU concentration was measured by liquid chromatography-mass spectrometry. A subset of 17 mice underwent DCE MRI with gadolinium contrast at baseline and one day after bev/omalizumab injection. Scans employed a three-dimensional spoiled gradient recalled sequence with tracer concentration estimated using variable flip-angle technique. Data analysis employed a conventional two-compartment tracer kinetic model.Results
Tumour 5FU concentration (µg/g) was significantly lower 1 day after bev (10mg/kg) compared to control (8.4 vs 21.6, p = 0.027). However, there was no significant difference in plasma 5FU concentration between the bev and control groups. Following bev (10mg/kg), DCE MRI measurements of tumour intravascular blood volume reduced by 38.3% (p = 0.01); there was no significant change in DCE-MRI parameters in the control group. Following bev (1mg/kg), tumour permeability-surface area product (ml/100ml/min) correlated with tumour 5FU concentration (r2 = 0.84, p = 0.01).Conclusion
Bev causes vascular shutdown consistent with its anti-angiogenic mode of action. Reduced tumour 5FU concentration suggests that the reported synergism between anti-VEGF and chemotherapy may not be attributable to improved drug delivery at this early time point. DCE-MRI may play a role as a biomarker for tumour drug concentration following anti-VEGF therapy.Disclosure
All authors have declared no conflicts of interest.