Sunitinib treatment did not affect BST To investigate the effect of sunitinib treatment on the function Major Tactics Over RKI-1447 Unveiled of tumor vasculature, first pass imaging movies were recorded, and BST images and BST frequency dis tributions were produced. BST was not affected by suni tinib treatment. This is shown qualitatively in Figure 6, which shows representative BST images and the corre sponding BST frequency distributions from day 2 and 4 of an untreated A 07 GFP tumor, an A 07 GFP tumor treated with sunitinib, an un treated R 18 GFP tumor, and an R 18 GFP tumor treated with sunitinib. The black re gion in the sunitinib treated A 07 GFP tumor reflects an avascular region which contains hypoxic tumor tissue.
Figure 7 shows BST for all tumors included in the short term treatment experiments, illus trating that untreated and sunitinib treated tumors did not differ in BST on either day 2 or 4, regardless of whether A 07 GFP tumors were treated with 20 mg kg day sunitinib, A 07 GFP tumors were treated with 40 mg kg day sunitinib, or R 18 GFP tumors were treated with 40 mg kg day sunitinib. Sunitinib treatment induced hypoxia To investigate the effect of sunitinib treatment on tumor hypoxia, tumors were resected and submitted to histo logical examination immediately after the last intravital microscopy imaging session. Untreated A 07 GFP tumors did not show hypoxic regions whereas sunitinib treated A 07 GFP tumors showed multiple hypoxic regions. The hypoxic regions co localized with avascular regions or regions with very low vessel density, and were found in both central and peripherial parts of sunitinib treated A 07 GFP tumors.
3 out of 6 untreated R 18 GFP tumors and 7 out of 8 sunitinib treated R 18 GFP tumors showed scat tered hypoxic regions. R 18 GFP tumors did not show avascular regions, and the hypoxic regions reflected low overall vessel densities. The hypoxic area fractions were significantly higher in sunitinib treated A 07 GFP tumors than in untreated A 07 GFP tumors, and a non significant trend towards higher hypoxic area fractions in sunitinib treated R 18 GFP tumors com pared to untreated R 18 GFP tumors was observed. Prolonged sunitinib treatment reduced tumor growth In a separate experiment, A 07 GFP tumors were treated with 40 mg kg day sunitinib or vehicle for 8 days.
By day 6, untreated tumors grew close to the window chamber boundaries, and mice bearing untreated tumors were sacri ficed to avoid growth restriction by the chamber prepara tions. Sunitinib treated tumors were significantly smaller, and were allowed to grow for two more days. The prolonged sunitinib treatment further reduced vessel densities, and increased interstitial distances, but did not affect BST. Our ex perimental model did not allow evaluation of longer treat ment periods.