Antisense oligodeoxynucleotide combination therapy of primary chronic myelogenous 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 require the expression of a functional MYC protein, suggesting an approach to treatment of Philadelphia leukemias based on simultaneous targeting 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 antisense phosphorothioate oligodeoxynucleotides ([S]ODNs), individually or in combination. Compared with antisense ODNs targeting of individual oncogenes, downregulation of both BCR-ABL and c-MYC by specific antisense [S]ODNs resulted in a synergistic antiproliferative effect. Colony formation of normal bone marrow cells was not affected by either treatment. To assess the therapeutic potential of multiple oncogene downregulation, 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 treated with individual compounds, the disease process was significantly retarded in the group treated with both [S]ODNs as revealed by flow cytometry, clonogenic assay, and RT-PCR analysis to detect leukemic cells in mouse tissue cell suspensions. These effects correlated with a markedly increased survival of leukemic mice treated with both antisense [S]ODNs. Leukemic cells harvested from antisense [S]ODN-treated mice were sensitive to the effects of antisense [S]ODNs in vitro, suggesting that the treatment can be successfully repeated. These data demonstrate the therapeutic potential of targeting multiple cooperating oncogenes.
Skorski
T
T
Kimmell Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Nieborowska-Skorska
M
M
Wlodarski
P
P
Zon
G
G
Iozzo
R V
RV
Calabretta
B
B
D000818:Animals; D001483:Base Sequence; D001752:Blast Crisis / Q000235:genetics / Q000628:therapy*; D002455:Cell Division / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D013873:Thionucleotides / Q000627:therapeutic use*; D014410:Tumor Stem Cell Assay
D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D016271:Proto-Oncogene Proteins c-myc; D013873:Thionucleotides; D016044:Fusion Proteins, bcr-abl