In vivo monitoring of sorafenib therapy effects on experimental prostate carcinomas using dynamic contrast-enhanced MRI and macromolecular contrast media

Purpose: To investigate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with macromolecular contrast media (MMCM) to monitor the effects of the multikinase inhibitor sorafenib on subcutaneous prostate carcinomas in rats with immunohistochemical validation. Materials and methods: Copenhagen rats, implanted with prostate carcinoma allografts, were randomized to the treatment group (n=8) or the control group (n=8). DCE-MRI with albumin-(Gd-DTPA)(35) was performed at baseline and after 1 week using a clinical 3-Tesla system. The treatment group received sorafenib, 10 mg/kg body weight daily. Kinetic analysis yielded quantitative parameters of tumor endothelial permeability surface area product (PS; m1/100 ml/min) and fractional blood volume (V-b, %). Tumors were harvested on day 7 for immunohistochemical analysis. Results: In sorafenib-treated tumors, PS (0.62 +/- 0.20 vs 0.08 +/- 0.09 ml/100 ml/min; P<0.01) and V-b (5.1 +/- 1.0 vs 0.56 +/- 0.48%; P<0.01) decreased significantly from day 0 to day 7. PS showed a highly significant inverse correlation with tumor cell apoptosis (TUNEL; r=-0.85, P<0.001). Good, significant correlations of PS were also observed with tumor cell proliferation (Ki-67; r=0.67, P<0.01) and tumor vascularity (RECA-1; r=0.72, P<0.01). MRI-assayed fractional blood volume V-b showed a highly significant correlation with tumor vascularity (RECA-1; r=0.87, P<0.001) and tumor cell proliferation (Ki-67; r=0.82, P<0.01). Conclusion: Results of DCE-MRI with MMCM demonstrated good, significant correlations with the immunohistochemically assessed antiangiogenic, antiproliferative, and proapoptotic effects of a 1-week, daily treatment course of sorafenib on experimental prostate carcinoma allografts.