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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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Effects of 1R-Chl on colony formation of CML patient MNCs and normal human MNCs.(A) MNCs from CML patients were cultured with rh stem cell factor, rh IL-3, rh GM-CSF with or without erythropoietin which lead to CFU-GM or BFU-E cell lineages. The experiments were done in duplicate with 1R-Chl ranging from 125 to 1000 nM, 1S-Chl at 500 and 1000 nM, and imatinib at 500 and 5000 nM. The colonies were counted and results were calculated as the percentage of the control plates (without treatment) after 2 weeks. (B) MNCs from normal donors were cultured and plated under the same condition as CML patient cells. The cells were exposed to 500 and 1000 nM 1R-Chl, 500 and 1000 nM 1S-Chl, and 500 and 5000 nM imatinib. The colonies were counted and percent growth inhibition was calculated after 2 weeks.
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pone-0003593-g002: Effects of 1R-Chl on colony formation of CML patient MNCs and normal human MNCs.(A) MNCs from CML patients were cultured with rh stem cell factor, rh IL-3, rh GM-CSF with or without erythropoietin which lead to CFU-GM or BFU-E cell lineages. The experiments were done in duplicate with 1R-Chl ranging from 125 to 1000 nM, 1S-Chl at 500 and 1000 nM, and imatinib at 500 and 5000 nM. The colonies were counted and results were calculated as the percentage of the control plates (without treatment) after 2 weeks. (B) MNCs from normal donors were cultured and plated under the same condition as CML patient cells. The cells were exposed to 500 and 1000 nM 1R-Chl, 500 and 1000 nM 1S-Chl, and 500 and 5000 nM imatinib. The colonies were counted and percent growth inhibition was calculated after 2 weeks.

Mentions: 1R-Chl, 1S-Chl, and imatinib were tested against bone marrow mononuclear cells from patients in chronic phase of CML. The cells were cultured in semisolid media containing different growth factors (rh stem cell factor, rh IL-3, rh GM-CSF with or without erythropoietin). Cells were exposed to 1R-Chl, 1S-Chl, and imatinib at different concentrations (Fig. 2A). The results show that exposing CML patient MNCs to 1R-Chl suppressed colony formation in both CFU-GM and BFU-E assays, while 1S-Chl was ineffective. Thus, 1R-Chl was effective against CML patient MNCs with an observed IC50 less than 125 nM, and in the murine BM experiments (Fig. 1). Potential non-specific toxicity of 1R-Chl was observed with normal human MNCs (Fig. 2B); however, such toxicity may be explained by the unusually high effectiveness of 1R-Chl against activated human MNCs.


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)

Effects of 1R-Chl on colony formation of CML patient MNCs and normal human MNCs.(A) MNCs from CML patients were cultured with rh stem cell factor, rh IL-3, rh GM-CSF with or without erythropoietin which lead to CFU-GM or BFU-E cell lineages. The experiments were done in duplicate with 1R-Chl ranging from 125 to 1000 nM, 1S-Chl at 500 and 1000 nM, and imatinib at 500 and 5000 nM. The colonies were counted and results were calculated as the percentage of the control plates (without treatment) after 2 weeks. (B) MNCs from normal donors were cultured and plated under the same condition as CML patient cells. The cells were exposed to 500 and 1000 nM 1R-Chl, 500 and 1000 nM 1S-Chl, and 500 and 5000 nM imatinib. The colonies were counted and percent growth inhibition was calculated after 2 weeks.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2571993&req=5

pone-0003593-g002: Effects of 1R-Chl on colony formation of CML patient MNCs and normal human MNCs.(A) MNCs from CML patients were cultured with rh stem cell factor, rh IL-3, rh GM-CSF with or without erythropoietin which lead to CFU-GM or BFU-E cell lineages. The experiments were done in duplicate with 1R-Chl ranging from 125 to 1000 nM, 1S-Chl at 500 and 1000 nM, and imatinib at 500 and 5000 nM. The colonies were counted and results were calculated as the percentage of the control plates (without treatment) after 2 weeks. (B) MNCs from normal donors were cultured and plated under the same condition as CML patient cells. The cells were exposed to 500 and 1000 nM 1R-Chl, 500 and 1000 nM 1S-Chl, and 500 and 5000 nM imatinib. The colonies were counted and percent growth inhibition was calculated after 2 weeks.
Mentions: 1R-Chl, 1S-Chl, and imatinib were tested against bone marrow mononuclear cells from patients in chronic phase of CML. The cells were cultured in semisolid media containing different growth factors (rh stem cell factor, rh IL-3, rh GM-CSF with or without erythropoietin). Cells were exposed to 1R-Chl, 1S-Chl, and imatinib at different concentrations (Fig. 2A). The results show that exposing CML patient MNCs to 1R-Chl suppressed colony formation in both CFU-GM and BFU-E assays, while 1S-Chl was ineffective. Thus, 1R-Chl was effective against CML patient MNCs with an observed IC50 less than 125 nM, and in the murine BM experiments (Fig. 1). Potential non-specific toxicity of 1R-Chl was observed with normal human MNCs (Fig. 2B); however, such toxicity may be explained by the unusually high effectiveness of 1R-Chl against activated human MNCs.

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