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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

Nilotinib is very effective in the treatment of Bcr/Abl-caused lymphoblastic leukemia in vivo. Survival of C57Bl/6J mice transplanted with 8093 lymphoma cells and treated either with nilotinib (n = 7; 75 mg/kg daily) or with vehicle (n = 8). Nilotinib-treated mice lived significantly (p < 0.01) longer than the control group.
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Figure 2: Nilotinib is very effective in the treatment of Bcr/Abl-caused lymphoblastic leukemia in vivo. Survival of C57Bl/6J mice transplanted with 8093 lymphoma cells and treated either with nilotinib (n = 7; 75 mg/kg daily) or with vehicle (n = 8). Nilotinib-treated mice lived significantly (p < 0.01) longer than the control group.

Mentions: Vehicle treated mice became moribund within 3 weeks of the transplantation. They showed clear symptoms of ALL. Nilotinib-treated mice lived statistically significantly longer as compared with the vehicle-treated mice (p < 0.05)(Fig. 2). This result clearly indicated that nilotinib was very effective in inhibiting the proliferation of the leukemic cells in vivo. However, also five of the seven drug-treated mice died. We ended treatment of the two remaining mice 51 days after the transplant of the leukemic cells, when all vehicle-treated mice had died. At this point both appeared normal. However, these two mice succumbed to leukemia 8 and 14 days later.


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)

Nilotinib is very effective in the treatment of Bcr/Abl-caused lymphoblastic leukemia in vivo. Survival of C57Bl/6J mice transplanted with 8093 lymphoma cells and treated either with nilotinib (n = 7; 75 mg/kg daily) or with vehicle (n = 8). Nilotinib-treated mice lived significantly (p < 0.01) longer than the control group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Nilotinib is very effective in the treatment of Bcr/Abl-caused lymphoblastic leukemia in vivo. Survival of C57Bl/6J mice transplanted with 8093 lymphoma cells and treated either with nilotinib (n = 7; 75 mg/kg daily) or with vehicle (n = 8). Nilotinib-treated mice lived significantly (p < 0.01) longer than the control group.
Mentions: Vehicle treated mice became moribund within 3 weeks of the transplantation. They showed clear symptoms of ALL. Nilotinib-treated mice lived statistically significantly longer as compared with the vehicle-treated mice (p < 0.05)(Fig. 2). This result clearly indicated that nilotinib was very effective in inhibiting the proliferation of the leukemic cells in vivo. However, also five of the seven drug-treated mice died. We ended treatment of the two remaining mice 51 days after the transplant of the leukemic cells, when all vehicle-treated mice had died. At this point both appeared normal. However, these two mice succumbed to leukemia 8 and 14 days later.

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