Suppression of Philadelphia1 leukemia cell growth in mice by BCR-ABL antisense oligodeoxynucleotide.
When injected into SCID mice, the Philadelphia chromosome-positive chronic myeloid leukemia-blast crisis cell line BV173 induces a disease process closely resembling that seen in leukemia patients. At 1 and 3 weeks after injection of 10(6) BV173 cells, CD10+ cells were detected in the bone marrow of the mice, leukemic colonies grew from bone marrow and spleen cell suspensions, and BCR-ABL transcripts were detectable in bone marrow, spleen, peripheral blood, liver, and lungs. Systemic treatment of the leukemic mice with a 26-mer BCR-ABL antisense oligodeoxynucleotide (1 mg/day for 9 days) induced disappearance of CD10+ and clonogenic leukemic cells and a marked decrease in BCR-ABL mRNA in mouse tissues. Untreated mice or mice treated with a BCR-ABL sense oligodeoxynucleotide or a 6-base-mismatched antisense oligodeoxynucleotide oligodeoxynucleotide were dead 8-13 weeks after leukemia cell injection; in marked contrast, mice treated with BCR-ABL antisense oligodeoxynucleotide died of leukemia 18-23 weeks after injection of leukemic cells. These findings provide evidence for the in vivo effectiveness of an anticancer therapy based on antisense oligodeoxynucleotides targeting a tumor-specific gene.
Skorski
T
T
Jefferson Cancer Institute, Philadelphia, PA.
Nieborowska-Skorska
M
M
Nicolaides
N C
NC
Szczylik
C
C
Iversen
P
P
Iozzo
R V
RV
Zon
G
G
Calabretta
B
B
D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis / Q000235:genetics*; D016313:Genes, abl; D006801:Humans; D007668:Kidney / Q000473:pathology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology*; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000633:toxicity; D016376:Oligonucleotides, Antisense / Q000032:analysis / Q000627:therapeutic use* / Q000633:toxicity*; D013154:Spleen / Q000473:pathology; D013997:Time Factors; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D016044:Fusion Proteins, bcr-abl