Positron emission tomography of murine liver metastases and the effects of treatment by combretastatin A-4

Abstract

There are major potential advantages in non-invasive measurement of preclinical tumour biology and therapeutic response in clinically relevant, internal body sites, notably the ability to follow outcome in individual animals rather than averaging results from groups. We have exploited positron emission tomography (PET) to determine the feasibility of detecting liver metastases in B6D2F1 mice using fluorine-18 fluorodeoxyglucose ([18F]FDG) both before and after treatment by the novel cytotoxic agent, combretastatin A-4. The normal distribution of [18F]FDG in the absence of disease was characterised, with the clear delineation of the brain, the heart and the urinary bladder in all studies. In untreated mice with liver metastases, a strong correlation (r2 = 0.98) was found between the quantitative estimates of [18F]FDG uptake obtained by analysis of PET images, and those obtained from ex vivo assay of liver plus metastases excised immediately after imaging. In this first series, the effective limit of resolution was in livers containing a number of small metastases (range 8-14) with a single volume equivalent of approximately 200 mm3. PET image analysis was concordant with histological measurements in showing that single intraperitoneal doses of combretastatin A-4 resulted in an average 30% volume destruction of metastatic mass by 24 h following administration.

Vascular Targeting Agents as Cancer Therapeutics

“…Magnetic resonance spectroscopy has been used to measure changes in tumor energy status as a reflection of changes in blood flow and tumor necrosis (23,128,129). High frequency Doppler ultrasound (61), dynamic computed tomography (130), and positron emission tomography (131,132) are also being studied. The feasibility of using positron emission tomography measurement of perfusion to assess VTA-induced changes in the vasculature of human tumors was reported recently (133).…”

The Utility of Micro-CT and MRI in the Assessment of Longitudinal Growth of Liver Metastases in a Preclinical Model of Colon Carcinoma

“…What are the most appropriate preclinical modalities and how does one optimize them for our given task—non-invasive study of liver metastases? Preclinical studies of mouse models of liver cancer have used several imaging modalities: positron emission tomography (PET) (2), bioluminescence imaging (3) (4), computed tomography (CT) (5), and magnetic resonance imaging (MRI) (6) (7) (8), albeit independently. PET provides excellent functional information regarding tumor metabolism.…”

Microvascular mechanisms by which the combretastatin A-4 derivative AC7700 (AVE8062) induces tumour blood flow stasis

“…It was first isolated from the bark of the South African bush willow by Pettit et al (1989), after which the water-soluble prodrug combretastatin A-4 phosphate (CA-4-P) was synthesised (Pettit et al, 1995), and the effects of CA-4 were studied in vivo (Dark et al, 1997). Combretastatin A-4 was determined to have strong suppressive effects on tumour blood flow (TBF) (Tozer et al, 1999), and its ability to induce widespread necrosis of solid tumours was described in several studies (Dark et al, 1997;Beauregard et al, 1998;Horsman et al, 1998;Tozer et al, 1999;Zhao et al, 1999;Landuyt et al, 2000;Malcontenti-Wilson et al, 2001). Recently, Tozer et al (2001Tozer et al ( , 2002 reported the mechanism of action of CA-4-P, which is currently undergoing phase I and phase II clinical trials (Dowlati et al, 2002).…”