ANTISENSE OLIGODEOXYNUCLEOTIDE COMBINATION THERAPY OF PRIMARY CHRONICMYELOGENOUS LEUKEMIA BLAST CRISIS IN SCID MICE

The proliferation of chronic myelogenous leukemia (CML) cells and the transformation of normal hematopoietic cells by BCR-ABL appear to requ ire the expression of a functional MYC protein, suggesting an approach to treatment of Philadelphia(1) leukemias based on simultaneous targe ting of BCR-ABL and c-MYC. To test this hypothesis, CML-blast crisis ( CML-BC) primary cells were treated in vitro with bcr-abl and c-myc ant isense phosphorothioate oligodeoxynucleotides ([S]ODNs), individually or in combination. Compared with antisense ODNs targeting of individua l oncogenes, downregulation of both BCR-ABL and c-MYC by specific anti sense [S]ODNs resulted in a synergistic antiproliferative effect. Colo ny formation of normal bone marrow cells was not affected by either tr eatment. To assess the therapeutic potential of multiple oncogene down regulation, SCID mice injected with CML-BC primary cells were treated systematically with equal doses of bcr-abl or c-myc antisense [S]ODNs or with a combination of both antisense [S]ODNs. Compared with mice tr eated with individual compounds, the disease process was significantly retarded in the group treated with both [S]ODNs as revealed by flow c ytometry, clonogenic assay, and RT-PCR analysis to detect leukemic cel ls in mouse tissue cell suspensions. These effects correlated with a m arkedly increased survival of leukemic mice treated with both antisens e [S]ODNs. Leukemic cells harvested from antisense [S]ODN-treated mice were sensitive to the effects of antisense [S]ODNs in vitro, suggesti ng that the treatment can be successfully repeated. These data demonst rate the therapeutic potential of targeting multiple cooperating oncog enes. (C) 1996 by The American Society of Hematology.