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Background:We aimed to test the ability of texture analysis to differentiate the spatial heterogeneity of 125I-A5B7 anti-carcinoembryonic antigen antibody distribution by nano-single photon emission computed tomography (SPECT) in well-differentiated (SW1222) and poorly differentiated (LS174T) hepatic metastatic colorectal cancer models before and after combretastatin A1 di-phosphate anti-vascular therapy.Methods:Nano-SPECT imaging was performed following tail vein injection of 20 MBq 125I-A5B7 in control CD1 nude mice (LS174T, n=3 and SW1222, n=4), and CA1P-treated mice (LS174T, n=3; SW1222, n=4) with liver metastases. Grey-level co-occurrence matrix textural features (uniformity, homogeneity, entropy and contrast) were calculated in up to three liver metastases in 14 mice from control and treatment groups.Results:Before treatment, the LS174T metastases (n=7) were more heterogeneous than SW1222 metastases (n=12) (uniformity, P=0.028; homogeneity, P=0.01; contrast, P=0.045). Following CA1P, LS174T metastases (n=8) showed less heterogeneity than untreated LS174T controls (uniformity, P=0.021; entropy, P=0.006). Combretastatin A1 di-phosphate-treated SW1222 metastases (n=11) showed no difference in texture features compared with controls (all P>0.05).Conclusions:Supporting the potential for novel imaging biomarkers, texture analysis of 125I-A5B7 SPECT shows differences in spatial heterogeneity of antibody distribution between well-differentiated (SW1222) and poorly differentiated (LS174T) liver metastases before treatment. Following anti-vascular treatment, LS174T metastases, but not SW1222 metastases, were less heterogeneous. [ABSTRACT FROM AUTHOR]

The development of strategies to combat hepatic disease and augment tissue regeneration has created a need for methods to assess regional liver function. Liver perfusion imaging has the potential to fulfil this need, across a range of hepatic diseases, alongside the assessment of therapeutic response. In this study, the feasibility of hepatic arterial spin labelling (HASL) was assessed for the first time in mice at 9.4 T, its variability and repeatability were evaluated, and it was applied to a model of colorectal liver metastasis. Data were acquired using flow-sensitive alternating inversion recovery-arterial spin labelling (FAIR-ASL) with a Look-Locker readout, and analysed using retrospective respiratory gating and a T1-based quantification. This study shows that preclinical HASL is feasible and exhibits good repeatability and reproducibility. Mean estimated liver perfusion was 2.2 ± 0.8 mL/g/min (mean ± standard error, n = 10), which agrees well with previous measurements using invasive approaches. Estimates of the variation gave a within-session coefficient of variation (CVWS) of 7%, a between-session coefficient of variation (CVBS) of 9% and a between-animal coefficient of variation (CVA) of 15%. The within-session Bland-Altman repeatability coefficient (RCWS) was 18% and the between-session repeatability coefficient (RCBS) was 29%. Finally, the HASL method was applied to a mouse model of liver metastasis, in which significantly lower mean perfusion (1.1 ± 0.5 mL/g/min, n = 6) was measured within the tumours, as seen by fluorescence histology. These data indicate that precise and accurate liver perfusion estimates can be achieved using ASL techniques, and provide a platform for future studies investigating hepatic perfusion in mouse models of disease. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

MFECP1 is a glycosylated recombinant fusion protein composed of MFE-23, a high-affinity anti-carcinoembryonic antigen (CEA) single chain Fv (scFv), fused to the enzyme carboxypeptidase G2 (CPG2), and has been constructed for use in antibody-directed enzyme pro-drug therapy (ADEPT). Radiolabelling of glycosylated MFECP1 with technetium-99m was developed for the purpose of determining tumour localisation of MFECP1 in a phase I ADEPT clinical study. The method used was 99mTc-carbonyl [99mTc(H2O)3(CO)3]+ (abbreviated to TcCO) mediated labelling of 99mTc to the hexahistidine (His) tag of MFECP1. MFECP1 fusion protein was labelled with TcCO under a variety of conditions, and this was shown to be a relatively simple and robust method. Tissue biodistribution was assessed in a CEA-expressing LS174T (human colon carcinoma) nude mouse xenograft model. Tissues were taken at 1, 4 and 6 h for assessment of distribution of radioactivity and for measurement of CPG2 enzyme levels. The amount of radioactivity retained by the tumour proved to be an accurate estimation of actual measured enzyme activity, indicating that this radiolabelling method does not appear to damage the antibody–antigen binding or the enzyme activity of MFECP1. However, correlation between CPG2 enzyme activity and measured radioactivity in liver, spleen and kidney was poor, indicating retention of radioactivity in non-tumour sites but loss of enzyme activity. The high retention of technetium radioisotope in normal tissues may limit the clinical applicability of this radiolabelling method for MFECP1; however, these results suggest that this technique does have applicability for measuring the biodistribution of His-tagged recombinant proteins. [ABSTRACT FROM AUTHOR]

Purpose: To develop a model that relates the pattern of dose delivery during radio-immunotherapy to biological effect. This model was used to assess the efficacy of a range of antibodies labelled with [sup 131]I, [sup 186]Re and [sup 90]Y. Materials and methods: Pharmacokinetic data were obtained by injecting tumour-bearing nude mice with radiolabelled antibody. The dose-rate in bone marrow and tumour was then given by a two-compartment model description of the pharmacokinetics combined with the radionuclide properties. Response characteristics of tumour and marrow were defined in terms of radiosensitivity, repair capacity and proliferation, and the biological effect was assessed using the linear-quadratic formulation. Results: Tumour-specific antibodies with intermediate molecular weight and clearance from the circulation delivered the most effective doses to tumour due to their rapid uptake and prolonged retention in tumour coupled with efficient clearance from blood. Matching the radionuclide with antibody pharmacokinetics and tumour type further increased this effect. Conclusions: The model improves conceptual understanding of the relationship of parameters affecting therapy and makes it possible to optimize radio-immunotherapy by selecting the most effective antibody and radionuclide according to tumour biology. [ABSTRACT FROM AUTHOR]

The in vivo antitumor activity of etoposide and mitozolomide was assessed in nude mice bearing a xenograft (CC3) of human gestational choriocarcinoma. Both agents demonstrated, at best, marginal activity observed as a delay in tumour growth. This lack of sensitivity suggests that the CC3 xenograft is not a good model for selection of agents for clinical evaluation in gestational choriocarcinoma. Plasma and tissue concentrations of etoposide and mitozolomide were measured in nude mice. Drug concentrations found in tumour tissue were 60% and 30% of plasma levels for mitozolomide and etoposide respectively. Etoposide and mitozolomide activity was also evaluated in vitro with another choriocarcinoma cell line (JAR). Maximum cell-kill was achieved after exposure to etoposide 0.05-1 microgram/ml for 3-24 h. In vitro response to etoposide demonstrates the importance of exposure time in determining cytotoxicity. In contrast, mitozolomide at concentrations from 1-100 micrograms/ml did not have a marked effect against JAR after exposure for 3-24 h. [ABSTRACT FROM AUTHOR]