title: A comparative study of PDGFR inhibition with imatinib on radiolabeled antibody targeting and clearance in two pathologically distinct models of colon adenocarcinoma.
abstract: The potential of radioimmunotherapy to selectively kill tumour cells is well established. However, optimisation is required with regards to increasing tumour localisation of antibodies. We used the PDGF-receptor inhibitor imatinib mesylate to improve tumour-specific antibody localisation in two models of colorectal adenocarcinoma and correlated antibody localisation with changes to tumour microvasculature. Mice bearing human colorectal xenografts (LS174T or SW1222) were treated with imatinib prior to administration of radiolabeled anti-CEA antibodies ((125)I-A5B7). Whole tumour and regional localisation of radiolabeled antibodies were measured. Microvessel density and pericyte coverage were quantified in whole tumours and correlated with (125)I-A5B7 localisation. Imatinib increased uptake of (125)I-A5B7 in LS174T but not SW1222 tumours after 48 h (p < 0.05). Imatinib reduced microvessel density in both models (p < 0.05) but reduced pericyte attachment to endothelial cells only in SW1222 xenografts (p < 0.05). Imatinib increases antibody distribution in LS174T tumours but not SW1222 tumours, and this correlated to changes in tumour microvessels. Accelerated clearance of radiolabeled antibody from normal tissues in both models resulted in enhanced tumour to normal tissue ratios. This improvement in tumour/normal tissue ratio has potential clinical benefit from a therapy and imaging perspective, and merits further investigation.
authors: Department of Oncology, UCL Cancer Institute, Paul O'Gorman Building, University College London, London WC1 6BT, UK. v.rajkumar@ucl.ac.uk
authors: Vineeth S
authors: VS
authors: Rajkumar
authors: Geoff
authors: G
authors: Boxer
authors: Mathew
authors: M
authors: Robson
authors: John
authors: J
authors: Muddle
authors: Yanni
authors: Y
authors: Papastavrou
authors: R Barbara
authors: RB
authors: Pedley
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D002272:Carcinoembryonic Antigen / Q000276:immunology; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D000068877:Imatinib Mesylate; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D016499:Radioimmunotherapy; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001549:Benzamides; D002272:Carcinoembryonic Antigen; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta