B182
Imatinib mesylate augments the selective targeting to tumour of radiolabeled anti-CEA antibodies from non-tumour tissues in LS174T and SW1222 xenografts
Vineeth Rajkumar, Mathew Robson, Geoff Boxer, Richard Begent, Barbara Pedley
UCL Cancer Institute, Paul O'Gorman Building, University College London, London, UK
Penetration of large molecular weight antibodies in solid tumours is impeded by physical barriers including high interstitial fluid pressure (IFP). Platelet derived growth factor (PDGF) is a critical regulator of IFP in solid tumours and a PDGF receptor inhibitor, imatinib mesylate decreases IFP in xenografts with a concomitant increase in tumour uptake of drugs and antibodies. However, the cellular mechanism of action is unclear.
Here, we consider the influence of differing tumour parameters by comparing the effect of imatinib mesylate on biosdistribution of a radiolabeled anti-CEA antibody (A5B7) in two contrasting human colorectal xenografts. SW1222 tumours are well differentiated and highly vascularised while LS174T tumours are moderately differentiated and poorly vascularised.
After 24 hours, imatinib increased the uptake of 125I-labeled A5B7 in LS174T (16.9% injected dose/gram) and SW1222 (22.2% injected dose/gram) tumours. After 120 hours, antibody uptake in imatinib treated LS174T tumours remained higher compared to controls, however, in SW1222 tumours, antibody uptake was decreased compared to controls. After 120 hours the tumour: non-tumour tissue ratio of antibody was increased in both models after imatinib treatment. After 120 hours tumour to liver (highest uptake in a non-tumour organ) ratios in untreated compared to treated animals for LS174T and SW1222 were increased from 14.7 to 21.1 and 26.2 to 27.8 respectively.
This data demonstrate clear differences in the effect of imatinib on antibody uptake between the two tumour models and suggest that imatinib may increase the clearance of antibody from normal tissue. Further studies investigating the mechanisms underlying these observations are ongoing.
