To prevent the resistance to Glivec in patients
with chronic myelogenous leukaemia (CML), it is necessary to get a good
understanding of its potential mechanisms. The present hypothesis accents
on the mechanisms whereby Bcr-Abl tyrosine kinase remains inhibited by
Glivec, but alternative signalling pathways become activated-the potential
reason associates with activation of telomerase after long-term treatment
with Glivec and recovery of cell proliferation and immortality. The hypothesis
is based on the observations about differences in telomere dynamics and
telomerase activity between chronic and blast phases of CML patients, as
well as about the potential effect of Glivec on the cross-talk between
telomerase, Bcr-Abl tyrosine kinase and protein kinase C family-key enzymes
in CML. It proceeds from recently published data, demonstrating that
protein kinase C activates and c-Abl tyrosine kinase inhibits telomerase.
During optimization of chemical structure, Glivec loose its effect on protein
kinase C and enhances the effect on Bcr-Abl tyrosine kinase, resulting in a
high potential to activate telomerase indirectly through its effect on both
kinases. Experimental preclinical data are given in confirmation of this
hypothesis.
