B181
Imatinib mesylate delays tumour regrowth after single dose CA-1-P therapy in LS174T but not SW1222 xenografts
Vineeth Rajkumar, Mathew Robson, Geoff Boxer, Richard Begent, Barbara Pedley
UCL Cancer Institute, Paul O'Gorman Building, University College London, London, UK
The vascular disrupting agent (VDA), CA-1-P causes the shutdown of established tumour vessels. A poorly understood feature of VDA induced vascular shutdown is the sparing of the microvessels in the peripheral rim of tumours. This viable rim leads to the rapid repopulation of tumours and explains why single dose therapy of VDAs produces either no or only modest tumour growth delays in animal models.
In the current study, we investigated whether tumour growth delay could be enhanced by inhibiting vascular regrowth after a single dose of CA-1-P. To test this hypothesis, we administered imatinib mesylate, a pericyte-targeting anti-angiogenic compound for 14 days after CA-1-P administration. Two contrasting human colorectal xenografts grown in MF1 nude mice were analysed. SW1222 tumours are well differentiated and highly vascularised while LS174T tumours are moderately differentiated and poorly vascularised.
At 14 days post-CA-1-P administration, imatinib treatment had significantly inhibited tumour growth in LS174T tumours compared to control tumours. No significant difference was observed in SW1222 xenografts after 14 days. Immunohistochemical analysis revealed in both LS174T and SW1222 models that microvascular density was reduced compared to untreated tumours.
This data suggests that imatinib treatment inhibits tumour regrowth in LS174T but not SW1222 xenografts after CA1P single dose therapy. Quantitative analysis of microvascular density, pericyte coverage, vessel perfusion and hypoxia are currently ongoing. Future studies will be aimed at investigating tumour regrowth at later time points and combining imatinib treatment with repeat dosing schedules of CA-1-P.
