For instance, tumors rebounded rapidly with Zd alone, but with ZdTha, tumor cells underwent increased apoptosis induced by Tha. This contributed to the total significant increase in necrosis quantified with ADC maps and finally verified with HE staining. Consequently, scientific assays the combined ZdTha showed a significantly smaller viable tumor rim on the CE-T1WIs. This finding was further supported with a stepwise linear regression analysis, which showed that the change in ADC at 12 d compared to baseline was the only independent predictor of tumor volume change with the combined therapy. Because ADC was negatively correlated with tumor volume change over time, an increase in ADC (fewer constraints on mobility) would indicate less viable cells and more necrosis.

Therefore, ADC represented a good imaging biomarker for evaluating tumor response after treatment [8], [9], [20], [34]. Another mechanism might be that Tha induced the rapid onset of functional tumor vessel normalization only when used in combination with Zd. In both preclinical and clinical studies, emerging evidence has supported the hypothesis that certain antiangiogenic agents transiently ��normalized�� the tumor vessel, which then improved oxygen and drug delivery [35]. In another report [36], Tha was found to induce vessel maturation by stimulating mural cell coverage; thus, Tha rescued vessel wall defects. The in vivo MRI methods [16] applied here demonstrated a significant reduction of Ktrans, i.e., a prolonged reduction of tumor vessel permeability. This was only found with ZdTha from 4 h to 6 d, but not with Zd or Tha alone.

Also, the ve decrease was transiently significantly stronger compared to controls from 4 h to 2 d, which could not be seen with Zd or Tha alone. A reduction of rBV from 4 h to 2 d and a transient increase in rBF after 2 d were also demonstrated with ZdTha. This was most likely due to the pruning and normalization of tumor vasculature. The functional information obtained from MRI-derived parameters provided imaging evidence Anacetrapib of vessel normalization induced by Tha [14]. The normalization window observed in our study was about 6 d, which was consistent with that reported in a previous study in mice [37]. Therefore, the effect of Zd may be maintained and enhanced due to improved blood flow induced by Tha, which improves oxygen and drug delivery during the normalization of tumor vessels [38]. There were some study limitations. First, imaging small animals with a clinical MR scanner was technically challenging, particularly for the liver, because abdominal respiratory movement in rats cannot be completely eliminated during MRI.