THE INFLUENCE OF OXYGEN-TENSION AND PH ON THE EXPRESSION OF PLATELET-DERIVED ENDOTHELIAL-CELL GROWTH-FACTOR THYMIDINE PHOSPHORYLASE IN HUMAN BREAST-TUMOR CELLS GROWN IN-VITRO AND IN-VIVO

We report that hypoxia regulates and influences the level of the angio genic enzyme platelet-derived endothelial cell growth factor (PD-ECGF) , also called thymidine phosphorylase, in vitro and in vivo, Levels of PD-ECGF protein increased 6-fold in the breast cancer cell line MDA 2 31 after 16 h of growth in 0.3% oxygen, A simultaneous increase in enz yme activity was observed, Immunohistochemical staining of MDA 231 tum ors grown in nu/nu mice showed increased expression of PD-ECGF in thos e parts of the tumor that are proximal to the areas of necrosis, In ad dition, increased and widespread staining for PD-ECGF protein was obta ined when the tumor vascular supply was occluded for 2 h by clamping, Lowering the media pH to 6.3-6.7 in vitro also resulted in an increase in PD-ECGF protein levels, This study demonstrates that tumor microen vironmental factors can result in the specific up-regulation of an ang iogenic enzyme that can also activate 5-fluorouracil prodrugs and henc e is exploitable therapeutically.