Microbubble destruction-reperfusion in the non-invasive measurement of the vascular targeting effects of the anti-cancer drug ZD6126

Abstract

A new and promising strategy in cancer therapy targets the proliferating endothelium of a tumour's blood vessels rather than the cells of the cancer itself. Among other advantages, such therapies may evade the drug resistance that many tumours acquire during treatment, rendering the drugs appropriate for long term use. However, because the tumour vasculature lies below the threshold of detection for conventional radiological techniques, new methods are required to determine the effect of such therapy on the tumour microvasculature. The combination of microbubble contrast and nonlinear imaging methods such as pulse inversion Doppler have been shown capable of detecting (but not resolving) flow at the capillary level. In this study, we use a combination of microbubble destruction-reperfusion flow measurement and real time contrast Imaging to assess the effects of an anti-vascular agent ZD6126 (AstraZeneca Inc, NJ) on experimental VX-2 tumours in the rabbit. The active component of this drug, N-acetyl colchinol, causes tubulin depolymerisation, thereby inducing neovascular endothelial cell rounding and subsequent vascular collapse. The effect is selective to tumour blood vessels (whose endothelial cells rely on tubulin for their structure) and is thought to be an acute one, occurring within hours of administration of the drug. Our objectives in this study were to make haemodynamic measurements of tumour blood flow rate and vascular volume, then to use these to determine dose response to the anti-vascular drug and to demonstrate the evolution of this effect with time following drug administration. We intended that the method used should employ a commercially available scanner and be suitable for translation to clinical contrast imaging of breast cancers.