Monitoring anti-angiogenic therapy in colorectal cancer murine model using dynamic contrast-enhanced MRI: comparing pixel-by-pixel with region of interest analysis.

Sorafenib is a multi-kinase inhibitor that blocks cell proliferation and angiogenesis. It is currently approved for advanced hepatocellular and renal cell carcinomas in humans, where its major mechanism of action is thought to be through inhibition of vascular endothelial growth factor and platelet-derived growth factor receptors. The purpose of this study was to determine whether pixel-by-pixel analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is better able to capture the heterogeneous response of Sorafenib in a murine model of colorectal tumor xenografts (as compared with region of interest analysis). MRI was performed on a 9.4 T pre-clinical scanner on the initial treatment day. Then either vehicle or drug were gavaged daily (3 days) up to the final image. Four days later, the mice were again imaged. The two-compartment model and reference tissue method of DCE-MRI were used to analyze the data. The results demonstrated that the contrast agent distribution rate constant (K(trans)) were significantly reduced (p < 0.005) at day-4 of Sorafenib treatment. In addition, the K(trans) of nearby muscle was also reduced after Sorafenib treatment. The pixel-by-pixel analysis (compared to region of interest analysis) was better able to capture the heterogeneity of the tumor and the decrease in K(trans) four days after treatment. For both methods, the volume of the extravascular extracellular space did not change significantly after treatment. These results confirm that parameters such as K(trans), could provide a non-invasive biomarker to assess the response to anti-angiogenic therapies such as Sorafenib, but that the heterogeneity of response across a tumor requires a more detailed analysis than has typically been undertaken.

Purification and chemical modifications of hemoglobin in developing hemoglobin based oxygen carriers.

The efficacy of blood substitutes, as a whole, has been readily demonstrated, in animals as well as clinical studies. It is well known that stroma free hemoglobin (SF-Hb) is very toxic, due to effects on renal and coagulation functions and vascular tone. Several modifications have been made to the hemoglobin tetramer in an attempt to eliminate its toxicity. Conjugation, cross-linking, polymerization, and recombinant technology have all been used to reduce toxicity, while aiming to optimize the therapeutic value of hemoglobin based blood substitutes. The remaining issue seems to be the hypertensive response seen in many hemoglobin solutions. The cause of the hypertensive response, and hence what chemical modifications are suitable to alleviate it are still under debate.