Treatment with a vascular disrupting agent does not increase recruitment of indium labelled human endothelial outgrowth cells in an experimental tumour model.

Lotte B Bertelsen,Anja B Bohn,Hans Stødkilde-Jørgensen,Lise Falborg,Michael R Horsman,Yuan Yuan Shen

doi:10.1186/1471-2407-14-903

Lotte B Bertelsen, Anja B Bohn + Show 4 more

Open Access

https://doi.org/10.1186/1471-2407-14-903

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Abstract

BackgroundThe effect of vascular disrupting agents in tumour therapy depends on both the immediate vascular shutdown, and on the following re-vascularization of the tumour. The aim of this study was to use a tumour model to investigate whether endothelial outgrowth cells (EOCs) influenced the short term treatment efficiency of combretastatin A-4 disodium phosphate (CA4P) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by increasing EOC tumour recruitment.MethodsIn order to visualize the recruitment of EOCs to the tumours, umbilical cord blood derived human EOCs were labelled with 111Indium-tropolone in a dose of 0.37 MBq pr 3×106 cells and were injected intravenously into mice carrying a C3H mammary carcinoma on their right rear foot. DMXAA and CA4P in different concentrations and at different exposure times were used to create a hypoxic environment in the C3H mammary carcinoma in the mice. Three different mice strains with various degrees of functional immune system were used to study the homing capability of EOCs.ResultsOur data showed that approximately 4% of the total injected radioactive dose per gram of tissue was found in the tumour after treatment with CA4P and DMXAA. Regardless of the concentration and the treatment duration, CA4P did not increase EOC recruitment to the tumour in comparison to EOC recruitment in control tumours in any of the 3 mice strains studied.ConclusionOur data showed that regardless of the grade of the immune system, ranging from a fully working to a fully compromised immune system, treatment with CA4P did not increase recruitment of xenotransplanted EOCs to tumour tissue.

Highlights

The effect of vascular disrupting agents in tumour therapy depends on both the immediate vascular shutdown, and on the following re-vascularization of the tumour
It is not fully settled to which extent Endothelial Progenitor Cells (EPCs) recruitment to the tumour occurs, the aim of the present study was to analyse the degree of homing of xenotransplanted 111Indium (111In) labelled endothelial outgrowth cells (EOCs) in tumour bearing mice after treatment with the vascular disrupting agents (VDA) compounds combretastatin A-4 disodium phosphate (CA4P) and dimethylxanthenone-4-acetic acid (DMXAA)
In vitro toxicity assay To investigate the effect of CA4P on EOCs, we treated EOCs in culture with medium or different doses of either the active compound combretastatin A4 (CA4) or the prodrug CA4P for 2 hours and followed the cell cultures for up to 6 days after treatment with VDA

Summary

Introduction

The effect of vascular disrupting agents in tumour therapy depends on both the immediate vascular shutdown, and on the following re-vascularization of the tumour. The demand of new vessel formation for expansion of tumour tissue has made the vasculature an obvious target for anti-tumour therapy both in the form of anti-angiogenic pharmaceuticals and by vascular disrupting agents (VDA) [19]. In this study we use the VDA compounds Combretastatin A-4 disodium phosphate (CA4P) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) both of which selectively mediate vascular shutdown of existing vasculature inside solid tumors [24,25]. These drugs exert their anti-vascular action in different approaches. DMXAA belongs to the group of flavonoids which induce secretion of cytokines [27] and recruitment of immune cells [28]

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