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Purpose: Comparison of the antiangiogenic/vascular properties of the oral mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) and the vascular endothelial growth factor receptor (VEGFR) inhibitor vatalanib (PTK/ZK). Experimental Design: Antiproliferative activity against various tumor histotypes and downstream effects on the mTOR pathway were measured in vitro. In vivo, antitumor activity, plasma, and tumor RAD001 levels were measured. Activity in several different angiogenic/ vascular assays in vitro and in vivo was assessed and compared with PTK/ZK.Results: RAD001 inhibited proliferation in vitro (IC 50 values <1 nmol/L to >1 Amol/L), and in sensitive and insensitive tumor cells, pS6 kinase and 4E-BP1were inhibited. Activity in vitro did not correlate with activity in vivo and significant responses were seen in tumors with IC 50 values >10-fold higher than tumor RAD001concentrations. In vitro, RAD001inhibited the proliferation of VEGF-stimulated and fibroblast growth factor-stimulated human endothelial cells but not dermal fibroblasts and impaired VEGF release from both sensitive and insensitive tumor cells but did not inhibit migration of human endothelial cells. In vivo, in tumor models derived from either sensitive or insensitive cells, RAD001 reduced Tie-2 levels, the amount of mature and immature vessels, total plasma, and tumorVEGF. RAD001did not affect blood vessel leakiness in normal vasculature acutely exposed to VEGF nor did it affect tumor vascular permeability (K trans ) as measured by dynamic contrast-enhanced magnetic resonance imaging. However, the pan-VEGFR inhibitor PTK/ZK inhibited endothelial cell migration and vascular permeability but had less effect on mature vessels compared with RAD001. Conclusions: VEGFR and mTOR inhibitors show similar but also distinct effects on tumor vascular biology, which has implications for their clinical activity alone or in combination.

Purpose:To investigate the physiological origins responsible for the varying blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI) responses to carbogen (95% O 2 /5% CO 2 ) breathing observed with different tumor types. Materials and Methods:Susceptibility contrast-enhanced MRI using the exogenous blood pool contrast agent NC100150 to determine blood volume and vessel size, and immunohistochemical-derived morphometric parameters, were determined in GH3 prolactinomas and RIF-1 fibrosarcomas, both grown in mice, which exhibited very different BOLD responses to carbogen.Results: Administration of NC100150 increased the R 2 * and R 2 rates of both tumor types, and indicated a significant four-fold larger blood volume in the GH3 tumor. The ratio ⌬R 2 */⌬R 2 showed that the capillaries in the GH3 were two-fold larger than those in the RIF-1, in agreement with morphometric analysis. Carbogen breathing induced a significant 25% decrease in R 2 * in the GH3 prolactinoma, whereas the response in the RIF-1 fibrosarcoma was negligible. Conclusion:Low blood volume and small vessel size (and hence reduced hematocrit) are two reasons for the lack of R 2 * change in the RIF-1 with carbogen breathing. BOLD MRI is sensitive to erythrocyte-perfused vessels, whereas exogenous contrast agents interrogate the total perfused vascular volume. BOLD MRI, coupled with a carbogen challenge, provides information on functional, hemodynamic tumor vasculature.