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Growth arrest of BCR-ABL positive cells with a sequence-specific polyamide-chlorambucil conjugate.

Chou CJ, O'Hare T, Lefebvre S, Alvarez D, Tyner JW, Eide CA, Druker BJ, Gottesfeld JM - PLoS ONE (2008)

Bottom Line: Imatinib, a selective inhibitor of the Bcr-Abl tyrosine kinase, has significantly improved the clinical outcome of patients with CML.However, subsets of patients lose their response to treatment through the emergence of imatinib-resistant cells, and imatinib treatment is less durable for patients with late stage CML.Chlorambucil has been used for treatment of B cell chronic lymphocytic leukemia, non-Hodgkin's and Hodgkin's disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.

ABSTRACT
Chronic myeloid leukemia (CML) is characterized by the presence of a constitutively active Abl kinase, which is the product of a chimeric BCR-ABL gene, caused by the genetic translocation known as the Philadelphia chromosome. Imatinib, a selective inhibitor of the Bcr-Abl tyrosine kinase, has significantly improved the clinical outcome of patients with CML. However, subsets of patients lose their response to treatment through the emergence of imatinib-resistant cells, and imatinib treatment is less durable for patients with late stage CML. Although alternative Bcr-Abl tyrosine kinase inhibitors have been developed to overcome drug resistance, a cocktail therapy of different kinase inhibitors and additional chemotherapeutics may be needed for complete remission of CML in some cases. Chlorambucil has been used for treatment of B cell chronic lymphocytic leukemia, non-Hodgkin's and Hodgkin's disease. Here we report that a DNA sequence-specific pyrrole-imidazole polyamide-chlorambucil conjugate, 1R-Chl, causes growth arrest of cells harboring both unmutated BCR-ABL and three imatinib resistant strains. 1R-Chl also displays selective toxicities against activated lymphocytes and a high dose tolerance in a murine model.

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Additive effects of 1R-Chl and imatinib treatments.(A) Murine BM cells transduced with unmutated BCR-ABL were treated with 500 nM imatinib, 500 nM 1R-Chl, and 500 nM 1S-Chl individually, or in combination of either 500 nM 1R-Chl or 500 nM 1S-Chl with 500 nM imatinib. (B) Same treatment routines were used on CML patient MNCs. The CML patient MNCs were treated 500 nM imatinib, 500 nM 1R-Chl, and 500 nM 1S-Chl individually, or 500 nM 1R(S)-Chl in combination with 500 nM imatinib. (C) Same experiments were done on normal blood donor MNCs.
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pone-0003593-g003: Additive effects of 1R-Chl and imatinib treatments.(A) Murine BM cells transduced with unmutated BCR-ABL were treated with 500 nM imatinib, 500 nM 1R-Chl, and 500 nM 1S-Chl individually, or in combination of either 500 nM 1R-Chl or 500 nM 1S-Chl with 500 nM imatinib. (B) Same treatment routines were used on CML patient MNCs. The CML patient MNCs were treated 500 nM imatinib, 500 nM 1R-Chl, and 500 nM 1S-Chl individually, or 500 nM 1R(S)-Chl in combination with 500 nM imatinib. (C) Same experiments were done on normal blood donor MNCs.

Mentions: The additive effects of 1R-Chl and imatinib were also studied in BCR-ABL transduced murine BM, CML patient MNCs, and normal human donor MNCs. Inhibition of colony formation by 1R-Chl and imatinib was additive in unmutated BCR-ABL-expressing murine BM (Fig. 3A). In MNCs from CML patients and normal blood donors, 1R-Chl was a stronger growth inhibitor than imatinib, and it appeared that 1R-Chl treatment alone at 500 nM is sufficient to completely (>90%) inhibit colony formation by these cells (Fig. 3B and 3C). The observed additive effects of 1R-Chl and imatinib indicate that a cocktail of 1R-Chl with imatinib could potentially increase the efficacy of imatinib treatment and prevent the emergence of imatinib-resistant CML cells. However, the strong colony formation inhibition of normal human MNCs by 1R-Chl could potentially indicate a non-specific toxicity response due to 1R-Chl. Further experiments on both murine BM and normal human donor MNCs were done to address this issue.


Growth arrest of BCR-ABL positive cells with a sequence-specific polyamide-chlorambucil conjugate.

Chou CJ, O'Hare T, Lefebvre S, Alvarez D, Tyner JW, Eide CA, Druker BJ, Gottesfeld JM - PLoS ONE (2008)

Additive effects of 1R-Chl and imatinib treatments.(A) Murine BM cells transduced with unmutated BCR-ABL were treated with 500 nM imatinib, 500 nM 1R-Chl, and 500 nM 1S-Chl individually, or in combination of either 500 nM 1R-Chl or 500 nM 1S-Chl with 500 nM imatinib. (B) Same treatment routines were used on CML patient MNCs. The CML patient MNCs were treated 500 nM imatinib, 500 nM 1R-Chl, and 500 nM 1S-Chl individually, or 500 nM 1R(S)-Chl in combination with 500 nM imatinib. (C) Same experiments were done on normal blood donor MNCs.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2571993&req=5

pone-0003593-g003: Additive effects of 1R-Chl and imatinib treatments.(A) Murine BM cells transduced with unmutated BCR-ABL were treated with 500 nM imatinib, 500 nM 1R-Chl, and 500 nM 1S-Chl individually, or in combination of either 500 nM 1R-Chl or 500 nM 1S-Chl with 500 nM imatinib. (B) Same treatment routines were used on CML patient MNCs. The CML patient MNCs were treated 500 nM imatinib, 500 nM 1R-Chl, and 500 nM 1S-Chl individually, or 500 nM 1R(S)-Chl in combination with 500 nM imatinib. (C) Same experiments were done on normal blood donor MNCs.
Mentions: The additive effects of 1R-Chl and imatinib were also studied in BCR-ABL transduced murine BM, CML patient MNCs, and normal human donor MNCs. Inhibition of colony formation by 1R-Chl and imatinib was additive in unmutated BCR-ABL-expressing murine BM (Fig. 3A). In MNCs from CML patients and normal blood donors, 1R-Chl was a stronger growth inhibitor than imatinib, and it appeared that 1R-Chl treatment alone at 500 nM is sufficient to completely (>90%) inhibit colony formation by these cells (Fig. 3B and 3C). The observed additive effects of 1R-Chl and imatinib indicate that a cocktail of 1R-Chl with imatinib could potentially increase the efficacy of imatinib treatment and prevent the emergence of imatinib-resistant CML cells. However, the strong colony formation inhibition of normal human MNCs by 1R-Chl could potentially indicate a non-specific toxicity response due to 1R-Chl. Further experiments on both murine BM and normal human donor MNCs were done to address this issue.

Bottom Line: Imatinib, a selective inhibitor of the Bcr-Abl tyrosine kinase, has significantly improved the clinical outcome of patients with CML.However, subsets of patients lose their response to treatment through the emergence of imatinib-resistant cells, and imatinib treatment is less durable for patients with late stage CML.Chlorambucil has been used for treatment of B cell chronic lymphocytic leukemia, non-Hodgkin's and Hodgkin's disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.

ABSTRACT
Chronic myeloid leukemia (CML) is characterized by the presence of a constitutively active Abl kinase, which is the product of a chimeric BCR-ABL gene, caused by the genetic translocation known as the Philadelphia chromosome. Imatinib, a selective inhibitor of the Bcr-Abl tyrosine kinase, has significantly improved the clinical outcome of patients with CML. However, subsets of patients lose their response to treatment through the emergence of imatinib-resistant cells, and imatinib treatment is less durable for patients with late stage CML. Although alternative Bcr-Abl tyrosine kinase inhibitors have been developed to overcome drug resistance, a cocktail therapy of different kinase inhibitors and additional chemotherapeutics may be needed for complete remission of CML in some cases. Chlorambucil has been used for treatment of B cell chronic lymphocytic leukemia, non-Hodgkin's and Hodgkin's disease. Here we report that a DNA sequence-specific pyrrole-imidazole polyamide-chlorambucil conjugate, 1R-Chl, causes growth arrest of cells harboring both unmutated BCR-ABL and three imatinib resistant strains. 1R-Chl also displays selective toxicities against activated lymphocytes and a high dose tolerance in a murine model.

Show MeSH
Related in: MedlinePlus