Enhanced Growth Suppression of Philadephia¹ Leukemia Cells in Mice by Targeting Both BCR-ABL and VEGF through the Antisense Strategy.

The Philadephia chromosome (Ph¹) translocation results in the formation of the BCR-ABL oncogene in over 95% patients with chronic myeloid leukemia (CML). VEGF levels are elevated both in the plasma of CML patients and in conditioned media taken from CML cells. Therefore, simultaneous targeting of BCR-ABL and VEGF might be a rational strategy for attempting treatment of Philadephia¹ leukemia. To test this hypothesis, we used an antisense strategy to downregulate BCR-ABL and VEGF expression in K562 cells, a human erythroleukemia cell line. In vitro, combination of bcr/abl and VEGF antisense oligodeoxyribonucleotides (AS-ODNs) exerted a specific synergistic antiproliferative effect on K562 cells and prominently sensitized K562 cells to apoptosis-inducing stimuli. In vivo, nude mice injected with K562 cells were treated systemically with BCR-ABL or VEGF AS-ODNs or with both ODNs in combination. In comparison with the mice treated with individual agents, the mice treated with both ODNs showed a slower growth of leukemia tumors, a reduction of microvessel density and an increased apoptosis in the tumors. These results demonstrate that targeting both BCR-ABL and VEGF may represent an excellent strategy to overcome the resistance to chemotherapeutic agents and ultimately to augment the efficacy of chemotherapy in CML.