SELECTIVE-INHIBITION OF CELL-PROLIFERATION AND BCR-ABL PHOSPHORYLATION IN ACUTE LYMPHOBLASTIC-LEUKEMIA CELLS EXPRESSING M-R-190,000 BCR-ABLPROTEIN BY A TYROSINE KINASE INHIBITOR (CGP-57148)
M. Beran et al., SELECTIVE-INHIBITION OF CELL-PROLIFERATION AND BCR-ABL PHOSPHORYLATION IN ACUTE LYMPHOBLASTIC-LEUKEMIA CELLS EXPRESSING M-R-190,000 BCR-ABLPROTEIN BY A TYROSINE KINASE INHIBITOR (CGP-57148), Clinical cancer research, 4(7), 1998, pp. 1661-1672
The excessive proliferation of the myeloid marrow compartment in Phila
delphia chromosome (Ph)-positive acute and chronic leukemias has been
largely attributed to a hyperactive and autonomously acting hybrid tyr
osine 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 chromos
ome 22, This specific molecular event, amenable to attack with specifi
cally designed inhibitors, has recently been successfully influenced b
y the drug CGP-57148 in mammalian cells transfected with full-length B
CR-ABL gene and expressing full-length p210(Bcr-Abl) protein, as well
as in primary human leukemic cells expressing p210(Bcr-Abl) fusion pro
tein. In view of the heterogeneity of BCR-ABL transcripts associated w
ith various phenotypes, we investigated the effect of CGP-57148 on p19
0(Bcr-Abl)- and p210(Br-Abl)-expressing, patient-derived cell. lines a
nd primary intact blast cells. In particular, we were interested in wh
ether the variations in molecular events and/or the phenotype of Ph-po
sitive cells would affect their susceptibility to the specific tyrosin
e kinase inhibitor CGP-57148, We have demonstrated that the sensitivit
y of human cells with lymphoblastic immunophenotype expressing p190(Bc
r-Abl) protein is comparable to that for leukemic myeloid cells expres
sing p210(Bcr-Abl) protein. After documenting profound and phenotype-i
ndependent suppression of both autophosphorylation and cell growth, we
explored the importance of time and dose of exposure on the manifesta
tion and stability of the induced events. Although there were variatio
ns between target cells, in vitro exposure for 24-48 h induced extensi
ve and apparently irreversible apoptosis in BCR-ABL-expressing but not
other normal or BCR-ABL-negative leukemic cells. These findings suppo
rt the potential use of CGP-57148 to purge Ph-positive cells from auto
logous bone marrow in vitro, Another important finding was the compara
ble suppressive effect of temporary CGP-57148 exposure on both clonoge
nic 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 pr
ove to be an important variable in the design of in vitro and in vivo
therapy using tyrosine kinase inhibitors.