Effects of the pyrimido-pyrimidine derivative RX-RA 85 on metastatic tumor cell-vascular endothelial cell interactions.
An important step in the metastatic process is the interaction of blood-borne malignant cells with the vascular endothelium. Among the agents that may interfere with this process are pyrimido-pyrimidines, such as RX-RA 85, developed originally as an antiplatelet agent. Using an endothelial cell momolayer attachment assay we have investigated the effects of RX-RA 85 on tumor cell and endothelial cell properties. Exposure of bovine aortic endothelial cells for 3 h to greater than 4 micrograms/ml RX-RA 85 produced toxic effects, resulting in vacuole formation, retraction and finally rounding up of the cells. Endothelial cells derived from different sources behaved dissimilarly; human brain, human meninges, mouse brain, mouse lung and rat lung endothelial cells were less sensitive to drug treatment than bovine aortic endothelial cells. RX-RA 85 treatment of bovine aortic endothelial cells increased B16-F1 melanoma cell adhesion. When B16-F1 cells were exposed to 4-8 micrograms/ml RX-RA 85, increased adhesion to the subendothelial matrix occurred, whereas exposure to higher drug concentrations (8-16 micrograms/ml RX-RA 85) decreased adhesion. Indirect immunofluorescence staining of cytoskeletal structures in B16-F1 cells adhering to and spreading on matrix revealed that the differential effects of RX-RA 85 on the organization of microtubules and microfilaments might explain the dose-dependent differences in adhesion kinetics.
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects; D004727:Endothelium / Q000187:drug effects / Q000473:pathology*; D005109:Extracellular Matrix / Q000502:physiology; D066298:In Vitro Techniques; D008546:Melanoma, Experimental / Q000473:pathology*; D009362:Neoplasm Metastasis; D011743:Pyrimidines / Q000494:pharmacology*
D011743:Pyrimidines; C042278:RX-RA 85