Non-invasive imaging of combretastatin activity in two tumor models: Association with invasive estimates

Abstract

Introduction. The efficacy of the vascular disrupting agent combretastatin A-4 phosphate (CA4P) depends on several factors including tumor size, nitric oxide level, interstitial fluid pressure, and vascular permeability. These factors vary among tumor types. The aim of this study was to investigate all these factors in two tumor models that respond differently to CA4P. Material and methods. Mice bearing C3H mammary carcinomas or KHT sarcomas (200 to 800 mm³) were intraperitoneally injected with CA4P (100 mg/kg). Tumor size and the effect of a nitric oxide inhibitor nitro-L-arginine (NLA) administered intravenously were evaluated by necrotic fraction histologically assessed at 24 hours. Interstitial fluid pressure (IFP) was measured using the wick-in-needle technique, and vascular characteristics were assessed with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results. Initial necrotic fraction was about 10% in both tumor models at 200 mm³, but only increased significantly with tumor size in the C3H mammary carcinoma. In this tumor, CA4P significantly induced further necrosis by about 15% at all sizes, but in the KHT tumor, the induced necrotic fraction depended on tumor size. For both tumor types, NLA with CA4P significantly increased necrotic fraction above that for each drug alone. CA4P significantly decreased IFP in all tumors except in the 800 mm³ C3H tumor, which had an initially non-significant lower value. Interstitial volume estimated by DCE-MRI increased in all groups, except the 800 mm³ C3H tumors. DCE-MRI vascular parameters showed different initial characteristics and general significant reductions following CA4P treatment. Conclusions. Both tumor models showed differences in all factors before treatment, and in their response to CA4P. Perfusion and permeability as estimated by DCE-MRI play a central role in the CA4P response, and interstitial volume and IFP seemed related. These factors may be of clinical value in the planning of CA4P treatments.

Acknowledgements

The authors would like to thank Ms. Inger Marie Horsman, Ms. Dorthe Grand, Ms. Pia Schjerbeck, and Mr. Mogens J. Johannsen for excellent technical assistance. Supported by the Danish Cancer Society, the Danish Research Agency, and CIRRO - The Lundbeck Foundation Center for Interventional Research in Radiation Oncology and The Danish Council for Strategic Research.

Declaration of interest: Michael R. Horsman is consultant for OXiGENE. The authors alone are responsible for the content and writing of the paper.