Effects of vascular endothelial growth factor receptor inhibitor SU5416 and prostacyclin on murine lung metastasis

The majority of patients with a diagnosis of cancer die from metastatic disease. Targeting specific steps in the metastatic process has the potential to improve patient outcomes. In this study, a novel lung metastasis model was developed by injecting Dil (1,1'-dioctadecyl-3,3,3,3'-tetramethylindocarbo-cyanine perchlorate)-labeled Lewis lung carcinoma cells into the tail vein of mice. The temporal development of tumor metastases was studied in the lung, liver and spleen. Additionally, the effects of vascular endothelial growth factor receptor inhibitor SU5416 and platelet activation inhibitor prostacyclin were tested in this metastasis model. Systemically injected Lewis lung carcinoma cells present in the lung at 15 min slowly accumulated in the liver and spleen reaching a peak at 4 days. After 8 days, tumor development was only evident in the lung. Use of SU5416 or prostacyclin lowered the initial density of Lewis lung carcinoma-labeled cells in the lung by a factor 1.8 and 2.3, respectively (P < 0.05). Furthermore, treatment with prostacyclin or SU5416 decreased lung weight by over 50% and the number of visible metastatic nodes by over 90% (P < 0.05). Combined treatment, resulted in grossly normal lung tissue. Additionally, systemic treatment with prostacyclin reduced harvested metastatic cell adherence to endothelial cells by a factor of 10 and treatment with SU5416 attenuated vascular formation (P < 0.001). In conclusion, SU5416 and prostacyclin effectively attenuated metastasis formation in this model. Dil labeling is an effective technique to monitor the temporal and spatial distribution of metastatic cells.