PURPOSE: The purpose of this study was to quantify and model the longitudinal intra-tumor physiological response to a single dose of a monoclonal antibody specific to the VEGFR2 using dynamic contrast-enhanced CT. MATERIAL AND METHODS: Dynamic contrast-enhanced CT imaging was performed on athymic nude mice bearing xenograft VEGF-transfected MCF-7 tumors (MCF7(VEGF)) to quantify intra-tumor physiology pre- and post-injection (days 2, 7, and 14) of a nonspecific (IgG1, controls) and specific (DC101, treated) monoclonal antibody targeting VEGFR2. Parametrical maps of tumor physiology-perfusion (F), permeability surface area (PS), fractional plasma (f(p)), and interstitial space (f (is))-were obtained at four time points over a 2-week period. RESULTS: A temporal multistage recovery process whereby a decoupling of the fractional change in physiological parameters (f (p), F) was observed when comparing treated to control tumors: f (p) and perfusion decreased by a combined 27% (P < 0.01) and 65% (P < 0.01) on day 2, while only perfusion remained reduced by 46% (P < 0.01) on day 7. Intra-tumor heterogeneity defined by the change in variance of perfusion decreased on days 2 and 7; no change in the variance of f(p) was observed. Analysis based on a mathematical model linking perfusion and vascular morphology indicates that a decrease in f(p) and perfusion was consistent with a reduction in blood vessel radius, followed by an increase in the vascular radius and tortuosity resulting in the decoupling of f(p) and perfusion before returning to control levels. CONCLUSION: Inhibiting VEGFR2 activity results in a temporal decoupling of physiological parameters, which can be explained by a combination of morphological changes influencing perfusion. Such a decoupling has the potential to significantly impact the delivery of pharmaceuticals and oxygen within solid tumors, critical factors in combined anti-angiogenic and radio- and chemotherapies.
PURPOSE: The purpose of this study was to quantify and model the longitudinal intra-tumor physiological response to a single dose of a monoclonal antibody specific to the VEGFR2 using dynamic contrast-enhanced CT. MATERIAL AND METHODS: Dynamic contrast-enhanced CT imaging was performed on athymic nude mice bearing xenograft VEGF-transfected MCF-7 tumors (MCF7(VEGF)) to quantify intra-tumor physiology pre- and post-injection (days 2, 7, and 14) of a nonspecific (IgG1, controls) and specific (DC101, treated) monoclonal antibody targeting VEGFR2. Parametrical maps of tumor physiology-perfusion (F), permeability surface area (PS), fractional plasma (f(p)), and interstitial space (f (is))-were obtained at four time points over a 2-week period. RESULTS: A temporal multistage recovery process whereby a decoupling of the fractional change in physiological parameters (f (p), F) was observed when comparing treated to control tumors: f (p) and perfusion decreased by a combined 27% (P < 0.01) and 65% (P < 0.01) on day 2, while only perfusion remained reduced by 46% (P < 0.01) on day 7. Intra-tumor heterogeneity defined by the change in variance of perfusion decreased on days 2 and 7; no change in the variance of f(p) was observed. Analysis based on a mathematical model linking perfusion and vascular morphology indicates that a decrease in f(p) and perfusion was consistent with a reduction in blood vessel radius, followed by an increase in the vascular radius and tortuosity resulting in the decoupling of f(p) and perfusion before returning to control levels. CONCLUSION: Inhibiting VEGFR2 activity results in a temporal decoupling of physiological parameters, which can be explained by a combination of morphological changes influencing perfusion. Such a decoupling has the potential to significantly impact the delivery of pharmaceuticals and oxygen within solid tumors, critical factors in combined anti-angiogenic and radio- and chemotherapies.
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