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Nilotinib treatment in mouse models of P190 Bcr/Abl lymphoblastic leukemia.

Kaur P, Feldhahn N, Zhang B, Trageser D, Müschen M, Pertz V, Groffen J, Heisterkamp N - Mol. Cancer (2007)

Bottom Line: In addition, culture of such cells ex vivo showed that they were as sensitive as the parental cell line to nilotinib but that the presence of stromal support allowed resistant cells to grow out.Visible lymphoma masses disappeared within six days of treatment and leukemic cell numbers in peripheral blood were significantly reduced.These results show that nilotinib has very impressive anti-leukemia activity but that lymphoblastic leukemia cells can become unresponsive to it both in vitro and in vivo through mechanisms that appear to be Bcr/Abl independent.

View Article: PubMed Central - HTML - PubMed

Affiliation: Section of Molecular Carcinogenesis, Division of Hematology/Oncology, Saban Research Institute, Childrens Hospital Los Angeles and the Keck School of Medicine, University of Southern California, Los Angeles, California, USA. pavinder@gmail.com

ABSTRACT

Background: Ph-positive leukemias are caused by the aberrant fusion of the BCR and ABL genes. Nilotinib is a selective Bcr/Abl tyrosine kinase inhibitor related to imatinib, which is widely used to treat chronic myelogenous leukemia. Because Ph-positive acute lymphoblastic leukemia only responds transiently to imatinib therapy, we have used mouse models to test the efficacy of nilotinib against lymphoblastic leukemia caused by the P190 form of Bcr/Abl.

Results: After transplant of 10,000 highly malignant leukemic cells into compatible recipients, untreated mice succumbed to leukemia within 21 days, whereas mice treated with 75 mg/kg nilotinib survived significantly longer. We examined cells from mice that developed leukemia while under treatment for Bcr/Abl kinase domain point mutations but these were not detected. In addition, culture of such cells ex vivo showed that they were as sensitive as the parental cell line to nilotinib but that the presence of stromal support allowed resistant cells to grow out. Nilotinib also exhibited impressive anti-leukemia activity in P190 Bcr/Abl transgenic mice that had developed overt leukemia/lymphoma masses and that otherwise would have been expected to die within 7 days. Visible lymphoma masses disappeared within six days of treatment and leukemic cell numbers in peripheral blood were significantly reduced. Treated mice survived more than 30 days.

Conclusion: These results show that nilotinib has very impressive anti-leukemia activity but that lymphoblastic leukemia cells can become unresponsive to it both in vitro and in vivo through mechanisms that appear to be Bcr/Abl independent.

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Related in: MedlinePlus

Comparative effect of nilotinib and imatinib on viability of three different lymphoma cell lines. (A), 8093; (B), B-1; (C), B-2. 3 × 106 lymphoma cells were seeded on 6-well tissue culture plates in the presence of E14.5 irradiated MEFs and cultured for 3 days. All cultures were simultaneously treated with the indicated concentrations of nilotinib or imatinib. Viability is defined as the percentage of viable cells/of the total number of cells. Each point represents mean of triplicate values ± standard error of the mean.
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Figure 1: Comparative effect of nilotinib and imatinib on viability of three different lymphoma cell lines. (A), 8093; (B), B-1; (C), B-2. 3 × 106 lymphoma cells were seeded on 6-well tissue culture plates in the presence of E14.5 irradiated MEFs and cultured for 3 days. All cultures were simultaneously treated with the indicated concentrations of nilotinib or imatinib. Viability is defined as the percentage of viable cells/of the total number of cells. Each point represents mean of triplicate values ± standard error of the mean.

Mentions: Nilotinib has been reported to be more potent than imatinib in inhibiting the proliferation of Bcr/Abl expressing cells [24-28]. To study its effectiveness in eliminating lymphoblastic leukemia cells in vitro, we compared 8093 lymphoblastic leukemia cells treated with different concentrations of nilotinib to the same cells treated with 5 μM imatinib. As shown in Fig. 1A, at the start of the drug treatment, all 8093 cells had a viability of >90%. Within 24 hours of treatment, this dropped to less than 45% under all treatment conditions. The effect of nilotinib treatment on cell viability was dose-dependent. 200 nM nilotinib treatment reduced the viability of the 8093 culture from >90% to 18% within 24 hours whereas treatment with 100 nM reduced viability to 28% within 24 hours. A lower dose of 50 nM left about 40% of the cells viable after the same time period. Cell viability was reduced to zero within 72 hours for all three concentrations of nilotinib.


Nilotinib treatment in mouse models of P190 Bcr/Abl lymphoblastic leukemia.

Kaur P, Feldhahn N, Zhang B, Trageser D, Müschen M, Pertz V, Groffen J, Heisterkamp N - Mol. Cancer (2007)

Comparative effect of nilotinib and imatinib on viability of three different lymphoma cell lines. (A), 8093; (B), B-1; (C), B-2. 3 × 106 lymphoma cells were seeded on 6-well tissue culture plates in the presence of E14.5 irradiated MEFs and cultured for 3 days. All cultures were simultaneously treated with the indicated concentrations of nilotinib or imatinib. Viability is defined as the percentage of viable cells/of the total number of cells. Each point represents mean of triplicate values ± standard error of the mean.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2169263&req=5

Figure 1: Comparative effect of nilotinib and imatinib on viability of three different lymphoma cell lines. (A), 8093; (B), B-1; (C), B-2. 3 × 106 lymphoma cells were seeded on 6-well tissue culture plates in the presence of E14.5 irradiated MEFs and cultured for 3 days. All cultures were simultaneously treated with the indicated concentrations of nilotinib or imatinib. Viability is defined as the percentage of viable cells/of the total number of cells. Each point represents mean of triplicate values ± standard error of the mean.
Mentions: Nilotinib has been reported to be more potent than imatinib in inhibiting the proliferation of Bcr/Abl expressing cells [24-28]. To study its effectiveness in eliminating lymphoblastic leukemia cells in vitro, we compared 8093 lymphoblastic leukemia cells treated with different concentrations of nilotinib to the same cells treated with 5 μM imatinib. As shown in Fig. 1A, at the start of the drug treatment, all 8093 cells had a viability of >90%. Within 24 hours of treatment, this dropped to less than 45% under all treatment conditions. The effect of nilotinib treatment on cell viability was dose-dependent. 200 nM nilotinib treatment reduced the viability of the 8093 culture from >90% to 18% within 24 hours whereas treatment with 100 nM reduced viability to 28% within 24 hours. A lower dose of 50 nM left about 40% of the cells viable after the same time period. Cell viability was reduced to zero within 72 hours for all three concentrations of nilotinib.

Bottom Line: In addition, culture of such cells ex vivo showed that they were as sensitive as the parental cell line to nilotinib but that the presence of stromal support allowed resistant cells to grow out.Visible lymphoma masses disappeared within six days of treatment and leukemic cell numbers in peripheral blood were significantly reduced.These results show that nilotinib has very impressive anti-leukemia activity but that lymphoblastic leukemia cells can become unresponsive to it both in vitro and in vivo through mechanisms that appear to be Bcr/Abl independent.

View Article: PubMed Central - HTML - PubMed

Affiliation: Section of Molecular Carcinogenesis, Division of Hematology/Oncology, Saban Research Institute, Childrens Hospital Los Angeles and the Keck School of Medicine, University of Southern California, Los Angeles, California, USA. pavinder@gmail.com

ABSTRACT

Background: Ph-positive leukemias are caused by the aberrant fusion of the BCR and ABL genes. Nilotinib is a selective Bcr/Abl tyrosine kinase inhibitor related to imatinib, which is widely used to treat chronic myelogenous leukemia. Because Ph-positive acute lymphoblastic leukemia only responds transiently to imatinib therapy, we have used mouse models to test the efficacy of nilotinib against lymphoblastic leukemia caused by the P190 form of Bcr/Abl.

Results: After transplant of 10,000 highly malignant leukemic cells into compatible recipients, untreated mice succumbed to leukemia within 21 days, whereas mice treated with 75 mg/kg nilotinib survived significantly longer. We examined cells from mice that developed leukemia while under treatment for Bcr/Abl kinase domain point mutations but these were not detected. In addition, culture of such cells ex vivo showed that they were as sensitive as the parental cell line to nilotinib but that the presence of stromal support allowed resistant cells to grow out. Nilotinib also exhibited impressive anti-leukemia activity in P190 Bcr/Abl transgenic mice that had developed overt leukemia/lymphoma masses and that otherwise would have been expected to die within 7 days. Visible lymphoma masses disappeared within six days of treatment and leukemic cell numbers in peripheral blood were significantly reduced. Treated mice survived more than 30 days.

Conclusion: These results show that nilotinib has very impressive anti-leukemia activity but that lymphoblastic leukemia cells can become unresponsive to it both in vitro and in vivo through mechanisms that appear to be Bcr/Abl independent.

Show MeSH
Related in: MedlinePlus