This is illustrated in Figure 2 which shows representative immunohistochemical preparations stained for microvessels (Figure 2A) and hypoxia (Figure 2B), and graphs illustrating the quantification of microvascular density, hypoxic fraction, necrotic fraction, and tumor IFP in untreated and sunitinib-treated tumors (Figure 2C-F). Sunitinib-treated tumors showed lower microvascular densities (Figure 2C; P < 0.0001), PLK inhibitor higher hypoxic fractions (Figure 2D; P = 0.045), and higher necrotic fractions (Figure 2E; P = 0.0015) than untreated

tumors. Sunitinib-treated tumors did not differ from untreated tumors in IFP (Figure 2F; P > 0.05). Figure 2 Sunitinib treatment affected tumor physiology. A-B, representative immunohistochemical preparations stained with BIIB057 mouse anti-CD31 antibody

to visualize microvessels (A) or anti-pimonidazole antibody to visualize hypoxic regions (B). The images show an untreated A-07 tumor (vehicle; left) and a sunitinib-treated A-07 tumor (sunitinib; right). C-F, microvascular density (MVD), hypoxic fraction, necrotic fraction, and IFP in untreated and sunitinib-treated A-07 tumors. Columns, BMS202 in vitro means of 11-15 tumors; bars, SEM. To investigate whether MRI could detect sunitinb-induced changes in tumor physiology, untreated and sunitinib-treated tumors were subjected to DW-MRI and DCE-MRI. ADC images and ADC frequency distributions were produced from DW-MRI data, and K trans images and K trans frequency distributions were produced from DCE-MRI series. Figure 3 shows the ADC image, the corresponding ADC frequency distribution, the K trans image, and the corresponding K trans frequency distribution of a representative untreated tumor (Figure 3A) and a representative sunitinib-treated tumor (Figure 3B).

Figure 4 shows average ADC (-)-p-Bromotetramisole Oxalate and average K trans of 15 untreated and 14 sunitinb-treated tumors, demonstrating that sunitinib-treated tumors showed significantly higher ADC values (Figure 4A; P < 0.0001) and significantly lower K trans values (Figure 4B; P = 0.0037) than untreated tumors. Figure 3 ADC and K trans images. ADC image, the corresponding ADC frequency distribution, K trans image, and the corresponding K trans frequency distribution of a representative untreated A-07 tumor (A) and a representative sunitinib-treated A-07 tumor (B). Color bars show ADC scale in 10-3 mm2/s or K trans scale in min-1. Vertical line in the frequency distributions shows median ADC or median K trans. Figure 4 Sunitinib treatment increased ADC and reduced K trans values. ADC (A) and K trans (B) in untreated and sunitinib-treated A-07 tumors. Columns, means of 14-15 tumors; bars, SEM. Discussion Sunitinib treatment did not reduce the growth of A-07 tumors, but despite this sunitinib-treated tumors showed altered vasculature and microenvironment and, interestingly, altered ADC and K trans values.