Fractionated 131I anti-CEA radioimmunotherapy: effects on xenograft tumour growth and haematological toxicity in mice.

Dose fractionation has been proposed as a method to improve the therapeutic ratio of radioimmunotherapy (RIT). This study compared a single administration of 7.4 MBq 131I-anti-CEA antibody given on day 1 with the same total activity given as fractionated treatment: 3.7 MBq (days 1 and 3), 2.4 MBq (days 1, 3, and 5) or 1.8 MBq (days 1, 3, 5, and 8). Studies in nude mice, bearing the human colorectal xenograft LS174T, showed that increasing the fractionation significantly reduced the efficacy of therapy. Fractionation was associated with a decrease in systemic toxicity as assessed by weight, but did not lead to any significant decrease in acute haematological toxicity. Similarly, no significant decrease in marrow toxicity, as assessed by colony-forming unit assays for granulocytes and macrophages (CFUgm), was seen. However, there was a significant depression of CFUgm counts when all treated animals were compared with untreated controls, suggesting that treatment did suppress marrow function. In conclusion, in this tumour model system, fractionated RIT causes less systemic toxicity, but is also less effective at treating tumours.

Technological advances in radioimmunotherapy.

Radioimmunotherapy (RIT) is a method of selectively delivering radionuclides with toxic emissions to cancer cells, while reducing the dose to normal tissues. Although primary tumours can often be treated successfully with external beam radiotherapy or surgery, metastases often escape detection and treatment, leading to therapy failure, and these can be treated with systemic targeted therapies such as RIT. This review describes more recent developments in the field, including both technological developments from the laboratory and increasingly encouraging findings from clinical studies.

Characterisation and radioimmunotherapy of L19-SIP, an anti-angiogenic antibody against the extra domain B of fibronectin, in colorectal tumour models.

Angiogenesis is a characteristic feature of tumours and other disorders. The human monoclonal antibody L19- SIP targets the extra domain B of fibronectin, a marker of angiogenesis expressed in a range of tumours. The aim of this study was to investigate whole body distribution, tumour localisation and the potential of radioimmunotherapy with the L19-small immunoprotein (SIP) in colorectal tumours. Two colorectal tumour models with highly different morphologies, the SW1222 and LS174T xenografts, were used in this study. Localisation and retention of the L19-SIP antibody at tumour vessels was demonstrated using immunohistochemistry and Cy3-labelled L19-SIP. Whole body biodistribution studies in both tumour models were carried out with (125)I-labelled L19-SIP. Finally, (131)I-labelled antibody was used to investigate the potential of radioimmunotherapy in SW1222 tumours. Using immunohistochemistry, we confirmed extra domain B expression in the tumour vasculature. Immunofluorescence demonstrated localisation and retention of injected Cy3-labelled L19-SIP at the abluminal side of tumour vessels. Biodistribution studies using a (125)I-labelled antibody showed selective tumour uptake in both models. Higher recorded values for localisation were found in the SW1222 tumours than in the LS174T (7.9 vs 6.6 %ID g(-1)), with comparable blood clearance for both models. Based on these results, a radioimmunotherapy study was performed in the SW1222 xenograft using (131)I-Labelled L19-SIP (55.5 MBq), which showed selective tumour uptake, tumour growth inhibition and improved survival. Radio- and fluorescence-labelled L19-SIP showed selective localisation and retention at vessels of two colorectal xenografts. Furthermore, (131)I-L19-SIP shows potential as a novel treatment of colorectal tumours, and provides the foundation to investigate combined therapies in the same tumour models.

Spatial accuracy of 3D reconstructed radioluminographs of serial tissue sections and resultant absorbed dose estimates.

Many agents using tumour-associated characteristics are deposited heterogeneously within tumour tissue. Consequently, tumour heterogeneity should be addressed when obtaining information on tumour biology or relating absorbed radiation dose to biological effect. We present a technique that enables radioluminographs of serial tumour sections to be reconstructed using automated computerized techniques, resulting in a three-dimensional map of the dose-rate distribution of a radiolabelled antibody. The purpose of this study is to assess the reconstruction accuracy. Furthermore, we estimate the potential error resulting from registration misalignment, for a range of beta-emitting radionuclides. We compare the actual dose-rate distribution with that obtained from the same activity distribution but with manually defined translational and rotational shifts. As expected, the error produced with the short-range 14C is much larger than that for the longer range 90Y; similarly values for the medium range 131I are between the two. Thus, the impact of registration inaccuracies is greater for short-range sources.