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Selective inhibition of cell proliferation and BCR-ABL phosphorylation in acute lymphoblastic leukemia cells expressing Mr 190,000 BCR-ABL protein by a tyrosine kinase inhibitor (CGP-57148).
Clin Cancer Res 1998; 4(7):1661-72CC

Abstract

The excessive proliferation of the myeloid marrow compartment in Philadelphia chromosome (Ph)-positive acute and chronic leukemias has been largely attributed to a hyperactive and autonomously acting hybrid tyrosine kinase BCR-ABL, a product of the fusion between the second exon of the c-ABL proto-oncogene and 5' portions of the BCR gene on chromosome 22. This specific molecular event, amenable to attack with specifically designed inhibitors, has recently been successfully influenced by the drug CGP-57148 in mammalian cells transfected with full-length BCR-ABL gene and expressing full-length p210Bcr-Abl protein, as well as in primary human leukemic cells expressing p210Bcr-Abl fusion protein. In view of the heterogeneity of BCR-ABL transcripts associated with various phenotypes, we investigated the effect of CGP-57148 on p190Bcr-Abl- and p210Bcr-Abl-expressing, patient-derived cell lines and primary intact blast cells. In particular, we were interested in whether the variations in molecular events and/or the phenotype of Ph-positive cells would affect their susceptibility to the specific tyrosine kinase inhibitor CGP-57148. We have demonstrated that the sensitivity of human cells with lymphoblastic immunophenotype expressing p190Bcr-Abl protein is comparable to that for leukemic myeloid cells expressing p210Bcr-Abl protein. After documenting profound and phenotype-independent suppression of both autophosphorylation and cell growth, we explored the importance of time and dose of exposure on the manifestation and stability of the induced events. Although there were variations between target cells, in vitro exposure for 24-48 h induced extensive and apparently irreversible apoptosis in BCR-ABL-expressing but not other normal or BCR-ABL-negative leukemic cells. These findings support the potential use of CGP-57148 to purge Ph-positive cells from autologous bone marrow in vitro. Another important finding was the comparable suppressive effect of temporary CGP-57148 exposure on both clonogenic KBM-5 cells and the whole cell population. Exposure time and dose appeared to be important variables among various cell types. Moreover, effective doses appeared uniformly harmless to cells lacking BCR-ABL protein functioning as tyrosine kinase. Thus, the continuous exposure of target cells, at least during the initial period of 24-48 h, may prove to be an important variable in the design of in vitro and in vivo therapy using tyrosine kinase inhibitors.

Authors+Show Affiliations

Leukemia Department, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9676840

Citation

Beran, M, et al. "Selective Inhibition of Cell Proliferation and BCR-ABL Phosphorylation in Acute Lymphoblastic Leukemia Cells Expressing Mr 190,000 BCR-ABL Protein By a Tyrosine Kinase Inhibitor (CGP-57148)." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 4, no. 7, 1998, pp. 1661-72.
Beran M, Cao X, Estrov Z, et al. Selective inhibition of cell proliferation and BCR-ABL phosphorylation in acute lymphoblastic leukemia cells expressing Mr 190,000 BCR-ABL protein by a tyrosine kinase inhibitor (CGP-57148). Clin Cancer Res. 1998;4(7):1661-72.
Beran, M., Cao, X., Estrov, Z., Jeha, S., Jin, G., O'Brien, S., ... Kantarjian, H. (1998). Selective inhibition of cell proliferation and BCR-ABL phosphorylation in acute lymphoblastic leukemia cells expressing Mr 190,000 BCR-ABL protein by a tyrosine kinase inhibitor (CGP-57148). Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 4(7), pp. 1661-72.
Beran M, et al. Selective Inhibition of Cell Proliferation and BCR-ABL Phosphorylation in Acute Lymphoblastic Leukemia Cells Expressing Mr 190,000 BCR-ABL Protein By a Tyrosine Kinase Inhibitor (CGP-57148). Clin Cancer Res. 1998;4(7):1661-72. PubMed PMID: 9676840.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective inhibition of cell proliferation and BCR-ABL phosphorylation in acute lymphoblastic leukemia cells expressing Mr 190,000 BCR-ABL protein by a tyrosine kinase inhibitor (CGP-57148). AU - Beran,M, AU - Cao,X, AU - Estrov,Z, AU - Jeha,S, AU - Jin,G, AU - O'Brien,S, AU - Talpaz,M, AU - Arlinghaus,R B, AU - Lydon,N B, AU - Kantarjian,H, PY - 1998/7/24/pubmed PY - 1998/7/24/medline PY - 1998/7/24/entrez SP - 1661 EP - 72 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 4 IS - 7 N2 - The excessive proliferation of the myeloid marrow compartment in Philadelphia chromosome (Ph)-positive acute and chronic leukemias has been largely attributed to a hyperactive and autonomously acting hybrid tyrosine kinase BCR-ABL, a product of the fusion between the second exon of the c-ABL proto-oncogene and 5' portions of the BCR gene on chromosome 22. This specific molecular event, amenable to attack with specifically designed inhibitors, has recently been successfully influenced by the drug CGP-57148 in mammalian cells transfected with full-length BCR-ABL gene and expressing full-length p210Bcr-Abl protein, as well as in primary human leukemic cells expressing p210Bcr-Abl fusion protein. In view of the heterogeneity of BCR-ABL transcripts associated with various phenotypes, we investigated the effect of CGP-57148 on p190Bcr-Abl- and p210Bcr-Abl-expressing, patient-derived cell lines and primary intact blast cells. In particular, we were interested in whether the variations in molecular events and/or the phenotype of Ph-positive cells would affect their susceptibility to the specific tyrosine kinase inhibitor CGP-57148. We have demonstrated that the sensitivity of human cells with lymphoblastic immunophenotype expressing p190Bcr-Abl protein is comparable to that for leukemic myeloid cells expressing p210Bcr-Abl protein. After documenting profound and phenotype-independent suppression of both autophosphorylation and cell growth, we explored the importance of time and dose of exposure on the manifestation and stability of the induced events. Although there were variations between target cells, in vitro exposure for 24-48 h induced extensive and apparently irreversible apoptosis in BCR-ABL-expressing but not other normal or BCR-ABL-negative leukemic cells. These findings support the potential use of CGP-57148 to purge Ph-positive cells from autologous bone marrow in vitro. Another important finding was the comparable suppressive effect of temporary CGP-57148 exposure on both clonogenic KBM-5 cells and the whole cell population. Exposure time and dose appeared to be important variables among various cell types. Moreover, effective doses appeared uniformly harmless to cells lacking BCR-ABL protein functioning as tyrosine kinase. Thus, the continuous exposure of target cells, at least during the initial period of 24-48 h, may prove to be an important variable in the design of in vitro and in vivo therapy using tyrosine kinase inhibitors. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/9676840/Selective_inhibition_of_cell_proliferation_and_BCR_ABL_phosphorylation_in_acute_lymphoblastic_leukemia_cells_expressing_Mr_190000_BCR_ABL_protein_by_a_tyrosine_kinase_inhibitor__CGP_57148__ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9676840 DB - PRIME DP - Unbound Medicine ER -