Definition and activity
Glivec ( Imatinib mesylate ) belongs to the class of inhibitors tyrosine kinases and represents an extraordinary medical progress in the treatment of CML for the ability to hit as "target" a specific cellular protein that is expressed only in leukemic cells, saving the non-neoplastic cells.
In fact Imatinib inhibites the Bcr-Abl (the specific marker of CML) because it competes with ATP.
Imatinib, as shown in vitro, has inhibitory activity also against the other two TK, c-kit (receptor for stem cell factor) and PDGF-R (receptor for PDGF),so it can be used as molecular therapy in neoplasms, hematologic and not, characterized by alteration of the c-kit (GIST, mastocytosis, idiopathic myelofibrosis, lung cancer and breast cancer, neuroblastoma) or PDGF-R (LMMCr, glioma, some solid tumors).
Sequencing treatment in chronic myeloid leukemia: the first choice may be the hardest. 2014
PDGF and its receptor.
PDGF is the major growth factor (both of competence of progression) for mesenchymal cells content in blood serum, where it passes during the coagulation for the disintegration of the granules of platelets. It operates also in producing fibroblast proliferation during the process of wound repair. It is a glicoprotide( weight 30-32 kDa) and it consists of two chains A and B (or PDGF-1 and PDGF-2) joined by means of a disulfide bridge. Each human plate contains an average of 1,000 PDGF molecules.
It joins to the connective cells by a receptor (PDGFR). Although PDGF appears specific for connective tissue cells, not all of these, however, contain the PDGFR, so that not all are able to respond to PDGF. (Among the cells without PDGFR: endothelial cells, lymphocytes, hematopoietic cells of the bone marrow). The PDGF receptor (PDGFR) is a protide able to autophosphorylate at tyrosine residues, taking protein kinase activity. The activation of protein kinase coincides with the fixation of the PDGF on the PDGFr. The receptors has an extracellular N-terminal domain which attaches the ligand, a single transmembrane alpha-helix and a C-terminal domain with the cytoplasmic protein-tyrosine kinase activity. The fixation of the ligands (for example, growth factors) to the extracellular domains of these receptors activates their cytosolic domains. Then there is the phosphorylation of both receptors themselves that of target proteins that propagate the signal initiated by the attack of the growth factor.
The steps in order are:
- ligand-induced receptor dimerization;
- autophosphorylation of the receptor.
Consequences of the autophosphorylation are:
- regulation by increasing the kinase activity of the receptor;
- creation of specific sites of attachment for other protein transduction, for the phosphorylation of tyrosine residues outside the catalytic domain.
The association of these molecules downstream signal with the receptor tyrosine kinase is mediated by protein domains that bind to specific peptides containing phosphotyrosine. The best characterized of these domains are called SH2 domains (consisting of approximately 100 aa).
This association leads to localize SH2-containing proteins to the plasma membrane, to enable the association with other proteins, to promote their phosphorylation and to stimulate their enzymatic activities.
The association of these proteins with autophosphorylated receptors therefore represents the first step in the transmission of intracellular signals initiated by the attack of growth factors to the cell surface.
Platelet-derived growth factor. Structure, function and roles in normal and trasformed cells. 1984
Imatinib can be used for the treatment of other diseases with alteration of PDGFR?
The inhibition of tyrosine kinases, including PDGFR, can reduce pulmonary artery pressure in pulmonary hypertension.
The study, called IMPRES
and performed against placebo, showed that, in patients with a form of advanced disease with high pulmonary resistance despite the use of other vasodilators, the molecule being tested has improved exercise capacity (six minutes test , predictor of survival in these patients).
In addition, imatinib appears to stem the uncontrolled growth of arterial smooth muscle cells, one of the causes of pulmonary arterial hypertension.
It seems that Imatinib can improve the condition of patients in more advanced stage although there are no data to suggest that it is able to stop the progression of the disease, which still continues.
So, it appears that imatinib mesylate may hold promise as an adjunct drug in PAH therapy!
Inhaled tyrosine kinase inhibitors for pulmonary hypertension: a possible future treatment. 2014