Different studies have shown that the efficacy of the vascular disrupting agent combretastatin A-4 disodium phosphate (CA4DP) can depend on a range of different factors including tumour size, nitric oxide, interstitial fluid pressure, and vascular permeability. These factors vary among tumour types. The aim of this study was to investigate all these factors in two tumour models previously shown to respond differently to CA4DP. C3H mammary carcinomas and KHT sarcomas were grown to volumes of 200 to 800 mm3 and treated with CA4DP intraperitoneally at a dose of 100 mg/kg. Tumour size and the effect of a nitric oxide inhibitor nitro-L-arginine (NLA) administered intravenously were evaluated by necrotic fraction assessed by histology. Interstitial fluid pressure (IFP) was measured using the wick-in-needle technique, and vascular characteristics were assessed with dynamic contrast enhanced magnetic resonance imaging. Initial necrotic fraction was about 10% in both tumours at 200 mm3, but only increased with tumour size in the C3H mammary carcinoma. In the C3H tumour, CA4DP induced further necrosis (about 15% of tumour volume) at all sizes, but in the KHT tumour, the induced necrotic fraction depended on tumour size. The increase in necrotic fraction caused by NLA given together with CA4DP was higher than the sum of the induced necrotic fractions induced by each drug given alone. CA4DP significantly decreased IFP in all tumours except in the 800 mm3 C3H tumour, which had an initially lower value (although not significantly). Interstitial volume estimated by DCE-MRI indicated an increase in all groups except the in the 800 mm3 C3H tumour such that IFP decrease and interstitial volume increase seemed related. DCE-MRI vascular parameters showed different initial characteristics and general significant reductions following CA4DP treatment. The two tumour models showed differences in all investigated factors before treatment as well as in their response to CA4DP. Perfusion plays a central role in the CA4DP response, and some factors appeared to be related. The investigated factors may be of clinical value in the planning of CA4DP treatments.
Afdeling for Eksperimentel Klinisk Onkologi, Århus Universitetshospital, Nørrebrogade 44, 8000 Århus C 2:
University of Newcastle Upon Tyne, Northern Institute for Cancer Research, Newcastle upon Tyne, U.K. 3:
MR-Centret, Århus Universitetshospital, Brendstrupgårdsvej 100, 8200 Århus N 4:
Neuroradiologisk Afdeling, Århus Universitetshospital, Nørrebrogade 44, 8000 Århus C 5:
Biomedicinsk Institut, Københavns Universitet, Blegdamsvej 3, 2200 København N