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Leukemia treatment in severe combined immunodeficiency mice by antisense oligodeoxynucleotides targeting cooperating
T Skorski1, M Nieborowska-Skorska, K Campbell
1Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Abstract:
Transformation of hematopoietic cells by the p210bcr/abl tyrosine kinase appears to require the expression of a functional MYC protein, suggesting that simultaneous targeting of BCR-ABL and c-myc might be a rational strategy for attempting treatment of Phil-adelphia leukemia. To test this hypothesis, severe combined immunodeficiency mice injected with Philadelphia leukemic cells were treated systemically with equal doses of bcr-abl or c-myc antisense oligodeoxynucleotides (ODNs) or with both ODNs in combination. Compared with the mice treated with individual agents, the disease process was much slower in the group treated with both ODNs, as revealed by flow cytometry, clonogenic assay, and reverse transcriptase-polymerase chain reaction analysis to detect leukemic cells in mouse tissue cell suspensions, and by enumeration of liver metastases. The retardation of the disease process was positively correlated with a markedly increased survival of leukemic mice treated with both ODNs. These data demonstrate the therapeutic potential of targeting multiple cooperating oncogenes.
Insights
Targeting both BCR-ABL and MYC oncogenes simultaneously with antisense oligodeoxynucleotides (ODNs) significantly slowed Philadelphia leukemia progression in mice. This combination therapy demonstrated therapeutic potential by improving leukemic mouse survival.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- The p210bcr/abl tyrosine kinase drives Philadelphia leukemia.
- MYC protein expression is essential for hematopoietic cell transformation by BCR-ABL.
Purpose of the Study:
- To investigate the therapeutic efficacy of simultaneously targeting BCR-ABL and c-MYC in Philadelphia leukemia.
- To evaluate the combined effect of bcr-abl and c-myc antisense oligodeoxynucleotides (ODNs) in a mouse model.
Main Methods:
- Severe combined immunodeficiency (SCID) mice bearing Philadelphia leukemic cells were treated with bcr-abl ODNs, c-myc ODNs, or a combination of both.
- Disease progression was monitored using flow cytometry, clonogenic assays, and reverse transcriptase-polymerase chain reaction (RT-PCR).
- Liver metastases were enumerated to assess disease burden.
Main Results:
- Combination therapy with both bcr-abl and c-myc ODNs significantly slowed leukemia progression compared to individual treatments.
- Leukemic cell detection in mouse tissues and liver metastases were reduced in the combination therapy group.
- Mice treated with both ODNs exhibited markedly increased survival rates.
Conclusions:
- Simultaneous targeting of cooperating oncogenes like BCR-ABL and MYC is a rational and effective therapeutic strategy for Philadelphia leukemia.
- Combination antisense ODN therapy holds significant therapeutic potential for treating Philadelphia leukemia.