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When the Bcl-2 oncogene which mediates inhibition of apoptosis [52], was transfected into tumor cells, tumor cell apoptosis decreased and VEGF expression increased significantly [48]. In another study, human osteosarcoma cells implanted in mice formed only microscopic avascular, dormant tumors, in which tumor cell proliferation was balanced by tumor cell apoptosis. When these cells were transfected with the ras oncogene, VEGF expression doubled, expression of thrombospondin decreased significantly, and large neovascularized tumors grew within approximately 2 weeks [7]. Thus, targeting oncogene products not only affects cancer cell proliferation and cell death, but also disrupts production of angiogenic factors. These studies predict that certain anti-cancer drugs developed for their capacity to block an oncogene product (for example, inhibitors of the EGF receptor tyrosine kinase), may have significant antiangiogenic activity [12,53,54]. For example, ras farnesyl transferase inhibitors block oncogene signaling pathways which up-regulate tumor cell production of VEGF and down-regulate production of the angiogenesis inhibitor, thrombospondin-1 [47].
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