Abstract
Background: The oral multikinase inhibitor sorafenib has been approved for the treatment of advanced HCC and metastatic RCC. Up to now, there is no data on its potential anti-angiogenic and antiproliferative effects on other tumor entities. Our aim was to investigate the anti-angiogenic effects of sorafenib on experimental prostate carcinomas in rats by dynamic contrast-enhanced MRI assays of endothelial permeability and tumor vascularity. Methods and Materials: 16 male Copenhagen rats were implanted with subcutaneous prostate carcinoma allografts (6 × 106 MLLB-2 cells in matrigel). The animals were imaged at baseline and after a one-week treatment course of sorafenib via gavage by dynamic MRI at 3.0T following enhancement with the prototype macromolecular contrast agent albumin-(Gd-DTPA). Quantitative MRI estimates of tumor microvessel permeability (transfer constant, 10–3 min–1) and tumor vascular richness (blood volume; %) were calculated based on a twocompartment kinetic model. Initial histological stainings of the issue for HE, RECA-1, Ki67, VEGF and TUNEL were done. Results: Endothelial permeability and blood volume in the tumors was significantly suppressed by Sorafenib over the treatment course of one week. The transfer constant in sorafenib-treated tumors (n = 8) yielded a significant decrease in endothelial permeability from baseline to day 7 (TCbaseline = 0.62 ± 0.20 to TCday7 = 0.08 ± 0.09; p < 0.01). The blood volume in sorafenib- treated tumors decreased significantly over the treatment course (BVbaseline = 5.1 ± 1.0 to BVday7 = 0.56 ± 0.48; p < 0.01). Histological analysis could show a significant reduction of vital tumor tissue (– 38 %, p < 0.03) due to an increasing of necrotic areas, Ki-67 positive cells (– 50 %, p < 0.02) and MVD. Significantly more TUNEL positive cells could be detected in sorafenib-treated tumors (+ 95.5 %, p < 0.01). Conclusion: Sorafenib significantly reduced endothelial permeability and tumor vascularity in a prostate cancer model as assayed by dynamic MRI enhanced with macromolecular contrast media. Results indicate a significant anti-angiogenic and anti-proliferative effect of sorafenib. Dynamic MRI enhanced could prove valuable for monitoring the anti-angiogenic effects of targeted therapy on an individual patient basis.
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Schwarz, E. et al. (2010). Dynamic Contrast-Enhanced MRI Monitoring proofs Inhibition of Tumor Growth and Angiogenesis by Sorafenib in an Experimental Tumor Model in Rats with immunohistological correlations. In: Gradinger, R., Menger, M., Meyer, HJ. (eds) Chirurgisches Forum und DGAV Forum 2010. Deutsche Gesellschaft für Chirurgie, vol 39. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-12192-0_44
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DOI: https://doi.org/10.1007/978-3-642-12192-0_44
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