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The sunitinib induced antiangiogenic effects were more pronounced selleck screening library for A 07 GFP tumors than for R 18 GFP tumors, and these differences pro bably reflected differences in the angiogenic profiles. Treatment induced reductions in vessel densities are expected to reduce tumor growth. In the present study, prolonged sunitinib treatment significantly reduced tumor growth, whereas short term sunitinib treatment did not affect tumor size. This observation illustrates that effects on tumor size generally are delayed com pared to the effects on tumor vasculature after antian giogenic treatment. Sunitinib treatment did not affect BST and, conse quently, improved vascular function was not observed in the current study.
Narrow, elongated, and tortuous tumor vessels are expected to elevate the geometric re sistance to blood flow, and a potential increase in vessel diameter, decrease in vessel segment length, or reduction in vessel tortuosity is expected to enhance tumor blood of sunitinib treatment on tumor vasculature and tumor oxygenation. The morphology of tumor vasculature was assessed by mapping tumor vascular networks with high resolution transillumination images and filters for green light. In these images only vessels with erythrocytes can be seen and, consequently, the morphological analysis was based on vessels with erythrocytes as opposed to dysfunctional flow. In the present study, we observed increased vessel segment lengths and unchanged vessel tortuosities after sunitinib treatment, and the remaining vessels in sunitinib treated tumors showed similar or smaller increases in vessel diameter than vessels in untreated tumors.
The effects on vascular morphology are thus in accordance with the observation that sunitinib treatment did not improve vascular function. Reduction in vessel density combined with no improvement of vascular function is expected to impair oxygen supply. In accord ance with this, sunitinib treatment induced hypoxia in A 07 GFP and R 18 GFP tumors. Interestingly, A 07 GFP tumors differed substantially from R 18 GFP tumors in vessel maturation. Our study thus illustrates that sunitinib treatment fails to improve vascular func tion in melanoma xenografts with both high and low degrees of vessel maturation. Sunitinib induced improvement of vascular function has been reported in a preclinical study of human gli oma xenografts.
In that study, increased red blood cell velocities were observed 2, 4, and 6 days after the start of sunitinib treatment. The time points where improved vascular function was observed in that study thus correspond well to the time points where BST was assessed in our study. Consequently, the lack of improved vascular function observed in our study was unlikely to be due to inadequate observation time points. Treatment with anti VEGF A or anti VEGFR 2 anti body has improved vascular function and tumor oxygen ation in some preclinical models.