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In vivo treatment of human leukemia in a scid mouse model with c-myb antisense oligodeoxynucleotides
M Z Ratajczak1, J A Kant, S M Luger
1Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104.
Abstract:
The c-myb protooncogene encodes proteins that are critical for hematopoietic cell proliferation and development. Disrupting c-myb function might, therefore, prove an effective therapeutic strategy for controlling leukemic cell growth. Antisense oligodeoxynucleotides have been utilized for this purpose in vitro, but their in vivo efficacy has not been reported. We therefore established human leukemia-scid mouse chimeras with K562 cells and treated diseased animals with phosphorothioate-modified antisense oligodeoxynucleotides. K562 cells express the c-myb protooncogene, which served as the target for the antisense DNA. They also express the tumor-specific bcr-abl oncogene that was utilized to track the human cells in the mouse host. Once circulating leukemic blast cells had been detected, the survival of untreated control mice was 6 +/- 3 days (mean +/- SD). The survival of animals treated for 7 or 14 days with either sense or scrambled-sequence c-myb oligodeoxynucleotides was not statistically different from the control animals. In distinct contrast, animals treated for similar lengths of time with antisense c-myb oligodeoxynucleotides survived at least 3.5 times longer than the various control animals. In addition, animals receiving antisense c-myb DNA had significantly less disease at the two sites most frequently manifesting leukemic cell infiltration, the central nervous system and the ovary. These results suggest that phosphorothioate-modified antisense DNA may be efficacious for the treatment of human leukemia in vivo, and by analogy, for the treatment of other human neoplasias.
Insights
Antisense oligodeoxynucleotides targeting the c-myb protooncogene significantly extended survival in a human leukemia mouse model. This suggests a potential new therapy for leukemia and other cancers.
Area of Science:
- Oncology
- Molecular Biology
- Hematology
Background:
- The c-myb protooncogene is crucial for hematopoietic cell development.
- Disrupting c-myb function is a potential strategy for leukemia treatment.
- In vivo efficacy of antisense oligodeoxynucleotides against c-myb has not been established.
Purpose of the Study:
- To evaluate the in vivo efficacy of antisense oligodeoxynucleotides targeting the c-myb protooncogene in a human leukemia mouse model.
Main Methods:
- Human leukemia-scid mouse chimeras were established using K562 cells.
- Diseased mice were treated with phosphorothioate-modified antisense c-myb oligodeoxynucleotides.
- K562 cells expressing c-myb and bcr-abl oncogenes were used to track human cells.
Main Results:
- Antisense c-myb oligodeoxynucleotide treatment resulted in a >3.5-fold increase in survival compared to controls.
- Sense or scrambled c-myb oligodeoxynucleotides did not improve survival.
- Significant reduction in leukemic infiltration was observed in the central nervous system and ovaries.
Conclusions:
- Phosphorothioate-modified antisense DNA targeting c-myb shows promise for treating human leukemia in vivo.
- This approach may be applicable to other human neoplasias.
