The mecha nism of tumor resistance to the monoclonal antibodies bevacizumab and cetuximab is not well understood and warrants further investigation. It is also possible that vandetanib MEK162 treatment may induce hemodynamic changes, such as normalization remode ling of the tumor vasculature as hypothesized by Jain, that would not necessarily be detected by estimating changes in Ktrans and iAUC60. More complex DCE MRI approaches such as the St Lawrence and Lee model, which is able to derive independent measurement of blood flow, blood volume and permeability surface area, may be more appropriate for detecting complex changes in tumor vascularity and hemodynamics. Normalization of the tumor vasculature might also be expected to improve tumor oxygenation and blood flow.

In this regard, the results from the exploratory assessment of T2 using intrinsic susceptibility MRI merit discussion. Changes in T2 can be used to monitor changes in deox yhemoglobin and an increase in T2 could Inhibitors,Modulators,Libraries result from improved tumor oxygenation and blood flow. However, T2 is influenced by other fac tors and is therefore a difficult parameter to interpret on its own. In the absence of detectable effects on tumor hemodynamics as measured by DCE MRI, an increase in T2 could be attributed to an increase in tumor cell death. As such, the significant increase in T2 at vandetanib 300 mg compared with 100 mg in the present study may reflect increased tumor necrosis at the higher dose. Further Inhibitors,Modulators,Libraries correlative work is needed to under stand the biological basis of changes in T2 in the clinical setting.

Population pharmacokinetic pharmacodynamic analyses showed no correlation between vandetanib exposure and any of the pharmacodynamic parameters analyzed. Given the long half life of vandetanib, it may take up to 4 weeks for vandetanib to reach steady state, in the present study, steady state was attained Inhibitors,Modulators,Libraries from day 15 at the earliest, but was mostly from day 22 onwards. It is not fully under stood how tumor growth adaptation during this pro longed period of drug accumulation may affect pharmacodynamic variables. Conclusion In the present study, DCE MRI assessments of iAUC60 and Ktrans provided no evidence that vandetanib modulated gadolinium uptake within the tumor vasculature of patients Inhibitors,Modulators,Libraries with advanced colorectal cancer and liver metas tases.

As discussed, these findings from a small open label study of only 24 patients should be interpreted with cau tion, particularly since vandetanib has previously demon strated evidence of antitumor activity in phase II studies in advanced NSCLC and medullary Inhibitors,Modulators,Libraries thyroid cancer that sellckchem is consistent with inhibition of VEGFR activity. Vandetanib is one of a number of VEGF signaling inhibitors in clinical development and each has a different pharmacological profile.