Abstract
In recent clinical studies, vascular disrupting agents (VDAs) are mainly used in combination with chemotherapy. However, an often overlooked concern in treatment combination is the VDA-induced impairment of chemotherapy distribution in the tumor. The work presented here investigated the impact of blood flow shutdown induced by Combretastatin A4 (CA4) on gemcitabine uptake into mouse hepatocarcinoma. At 2 h after CA4 treatment, using DCE-MRI, a significant decrease in the perfusion-relevant parameters Ktrans and Vp were observed in treated group compared with the control group. The blood flow shutdown was indeed confirmed by a histology study. In a third experiment, the total gemcitabine uptake was found to be significantly lower in treated tumors, as assessed in a separate experiment using ex vivo fluorine nuclear magnetic resonance spectroscopy. The amount of active metabolite gemcitabine triphosphate was also lower in treated tumors. In conclusion, the blood flow shutdown induced by VDAs can impact negatively on the delivery of small cytotoxic agents in tumors. The present study outlines the importance of monitoring the tumor vascular function when designing drug combinations.
Highlights
Tumor vasculature is an attractive target in anticancer therapy because of its critical role in tumor growth, development, and metastasis (Folkman, 1995)
Combretastatin A4 (CA4) acts as a tubulin-binding agent, leading to a destabilization of the tubulin polymers of the cytoskeleton of proliferating endothelial cells
We demonstrate that a negative modulation of tumor blood flow by CA4 treatment causes a significant decrease in gemcitabine delivery in a solid tumor mouse model
Summary
Tumor vasculature is an attractive target in anticancer therapy because of its critical role in tumor growth, development, and metastasis (Folkman, 1995). Unlike antiangiogenic agents, which prevent the development of new blood vessels, vascular disrupting agents (VDAs) target the established tumor vasculature causing a rapid collapse in tumor blood flow leading to secondary extensive tumor necrosis (Thorpe, 2004; Tozer et al, 2005). Several preclinical studies have shown that VDAs induce necrosis in the poorly perfused core regions but spare tumor cells in periphery (Blakey et al, 2002; Chaplin and Hill, 2002; Siemann, 2011). This “viable rim” forms the rationale for combination approaches since VDAs affect the central part of the tumor that is often resistant to conventional therapies, whereas conventional. VDAs are mainly used in combination with chemotherapy in current clinical studies
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