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

Abstract

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; ml/100 ml/min) and fractional blood volume (Vb, %). 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 Vb (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 Vb 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.

Vascular response patterns to targeted therapies in murine breast cancer models with divergent degrees of malignancy

“…For future studies, reduction in temporal in favor of spatial resolution could be performed to further assess intratumoral heterogeneity, a main contributor to malignant tumor progression, metastasis formation and therapy resistance [ 56 ]. For precise analysis of not only tumor perfusion but also permeability, numerous studies have demonstrated that macromolecular contrast agents (MMCA) are more favorable than small molecular contrast agents (SMCA) [ 57 – 59 ]. While SMCAs have an unselective extracellular extravasation profile and already extravasate in physiological tissue, MMCAs follow an intravascular distribution profile and are only able to extravasate when the endothelial permeability is pathologically enhanced, as known in tumor vasculature.…”

Contrast agents in dynamic contrast-enhanced magnetic resonance imaging

“…DCE-MRI with albumin-(Gd-DTPA) 45 can detect the early effects on tumor microvasculature of a potentially curative treatment in experimental soft-tissue sarcomas [ 55 ]. Moreover, DCE-MRI monitoring of sorafenib therapy effects on experimental prostate carcinomas with albumin-(Gd-DTPA) 35 showed significant correlations with anti-angiogenic, anti-proliferative and proapoptotic effects determined immunohistochemically [ 56 ]. A DCE-MRI study assessing anti-PDGFR therapy effects in a prostate cancer bone metastasis model with biotin-labeled albumin-Gd-DTPA showed a reduction in vascular permeability and provided insights into the role played by VEGF in anti-PDGFR therapy [ 57 ].…”

DCE-MRI for Early Prediction of Response in Hepatocellular Carcinoma after TACE and Sorafenib Therapy: A Pilot Study

“…Functional imaging methods can help solve these problems. Dynamic contrast-enhanced MRI (DCE-MRI) appears to be well correlated with immunohistochemical findings of antiangiogenic, antiproliferative and proapoptotic effects [ 7 ]. DCE-MRI can measure the changes in tumor blood flow, vascular permeability and interstitial and intravascular volume that result from these effects.…”